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1,785 results on '"Structural Genomics Consortium"'

1. Towards proteome scale antibody selections using phage display

Author: Mersmann, Michael, Meier, Doris, Mersmann, Jana, Helmsing, Saskia, Nilsson, Peter, Gräslund, Susanne, Structural Genomics Consortium, Colwill, Karen, Hust, Michael, and Dübel, Stefan
Published: 2010
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2. Towards proteome scale antibody selections using phage display

Author: Michael Mersmann, Doris Meier, Jana Mersmann, Saskia Helmsing, Peter Nilsson, Susanne Gräslund, null Structural Genomics Consortium, Karen Colwill, Michael Hust, and Stefan Dübel
Subjects: Phage display, Proteome, Bioengineering, Enzyme-Linked Immunosorbent Assay, General Medicine, Computational biology, Biology, Molecular biology, Antibodies, Structural genomics, Antigen, Peptide Library, Protein microarray, Genomic library, Panning (camera), Peptide library, Molecular Biology, Biotechnology
Abstract: In vitro antibody generation by panning a large universal gene library with phage display was employed to generate antibodies to more than 60 different antigens. Of particular interest was a comparison of pannings on 20 different SH2 domains provided by the Structural Genomics Consortium (SGC). Streamlined methods for high throughput antibody generation developed within the 'Antibody Factory' of the German National Genome Research Network (NGFN) were demonstrated to minimise effort and provide a reliable and robust source for antibodies. For the SH2 domains, in two successive series of selections, 2668 clones were analysed, resulting in 347 primary hits in ELISA. Half of these hits were further analysed, and more than 90 different scFv antibodies to all antigens were identified. The validation of selected antibodies by cross-reactivity ELISA, western blot and on protein microarrays demonstrated the versatility of the in vitro antibody selection pipeline to generate a renewable resource of highly specific monoclonal binders in proteome scale numbers with substantially reduced effort and time.
Published: 2009

3. Structural basis for substrate recognition by the human N-terminal methyltransferase 1

Author: Min, Jinrong [Univ. of Toronto, ON (Canada). Structural Genomics Consortium. Dept. of Physiology]
Published: 2015
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4. System-Wide Modulation of HECT E3 Ligases with Selective Ubiquitin Variant Probes

Author: Emmanuel Lemichez, Brenda A. Schulman, Zhenyue Hao, Sachdev S. Sidhu, Nan Li, Ryan Murchie, Wei Zhang, Maria A. Sartori, Kuen-Phon Wu, Jason Moffat, John R. Walker, Avinash Persaud, Yi Sheng, Alban Ordureau, Jicheng Hu, Chong Jiang, Manjeet Mukherjee, Kevin R. Brown, Yufeng Tong, Yanjun Li, Junjie Chen, Anne Doye, Peter Y. Mercredi, Daniela Rotin, Hari B. Kamadurai, J. Wade Harper, Donnelly Center Cellular and Biomolecular Research [Univ. Toronto], University of Toronto, St Jude Children's Research Hospital, Department of Cell Biology, Harvard Medical School [Boston] (HMS), Program in Cell Biology [Toronto], The Hospital for sick children [Toronto] (SickKids)-Department of Biochemistry [University of Toronto], University of Toronto-University of Toronto, Structural Genomics Consortium, The University of Texas M.D. Anderson Cancer Center [Houston], Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of York [York, UK], Campbell Family Institute for Breast Cancer Research, University Health Network, Department of Pharmacology and Toxicology [Toronto], Department of Molecular Genetics [Toronto], The Donnelly Centre for Cellular and Biomolecular Research [Toronto, ON, Canada] (CCBR), J.W.H. was supported by NIH (R37NS083524 and GM095567). A.O. was supported by an Edward R. and Anne G. Lefler Center postdoctoral fellowship. J.W.H. is a consultant for Millennium: the Takada Oncology Company and Biogen. D.R. holds a Canada Research Chair (Tier 1 in Biochemistry and Signal Transduction) and was supported by CIHR (MOP#130422). B.A.S. is an investigator of the Howard Hughes Medical Institute (HHMI) and was supported by ALSAC, NIH R37GM065930 and P30CA021765. NECAT and APS were supported by NIH P41 GM103403 and DOE Contract DE-AC02-06CH11357. W.Z. was supported by a CIHR postdoctoral fellowship. S.S.S. and J.M. were supported by CIHR (MOP#111149 and 136956). The Structural Genomics Consortium (SGC) is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA) (ULTRA-DD grant no. 115766), Janssen, Merck & Co., Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation-FAPESP, Takeda, and the Wellcome Trust., and We thank members of the Sidhu and Schulman groups for helpful comments. We thank Andrew Vorobyov, Eva Chou, Yogesh Hooda, Jun Gu, and Aiping Dong for technical assistance. We are indebted to Pankaj Garg, Andreas Ernst, Abiodun Ogunjimi, Clare Jeon, Satra Nim, Frank Sicheri, and Hongrui Wang for reagents and advice.
Subjects: Models, Molecular, 0301 basic medicine, Subfamily, [SDV]Life Sciences [q-bio], MESH: Catalytic Domain, NEDD4, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], MESH: Ubiquitin/chemistry, MESH: Ubiquitin/metabolism, Madin Darby Canine Kidney Cells, MESH: Dogs, Ubiquitin, Cell Movement, Catalytic Domain, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], MESH: Animals, MESH: Cell Movement, chemistry.chemical_classification, MESH: Organoids/metabolism, biology, MESH: Ubiquitin-Protein Ligases/chemistry, Cell migration, Cell biology, MESH: Ubiquitin/genetics, Organoids, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Models, Molecular, MESH: HCT116 Cells, Ubiquitin-Protein Ligases, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, macromolecular substances, Cell Line, 03 medical and health sciences, Dogs, Peptide Library, Animals, Humans, Molecular Biology, NEDD4L, DNA ligase, MESH: Humans, MESH: Organoids/cytology, MESH: Madin Darby Canine Kidney Cells, MESH: Ubiquitin-Protein Ligases/metabolism, Cell Biology, HCT116 Cells, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Cell Line, 030104 developmental biology, chemistry, biology.protein, MESH: Peptide Library, Genetic screen
Abstract: Comment in : A Billion Ubiquitin Variants to Probe and Modulate the UPS. [Mol Cell. 2016]; International audience; HECT-family E3 ligases ubiquitinate protein substrates to control virtually every eukaryotic process and are misregulated in numerous diseases. Nonetheless, understanding of HECT E3s is limited by a paucity of selective and potent modulators. To overcome this challenge, we systematically developed ubiquitin variants (UbVs) that inhibit or activate HECT E3s. Structural analysis of 6 HECT-UbV complexes revealed UbV inhibitors hijacking the E2-binding site and activators occupying a ubiquitin-binding exosite. Furthermore, UbVs unearthed distinct regulation mechanisms among NEDD4 subfamily HECTs and proved useful for modulating therapeutically relevant targets of HECT E3s in cells and intestinal organoids, and in a genetic screen that identified a role for NEDD4L in regulating cell migration. Our work demonstrates versatility of UbVs for modulating activity across an E3 family, defines mechanisms and provides a toolkit for probing functions of HECT E3s, and establishes a general strategy for systematic development of modulators targeting families of signaling proteins.
Published: 2016

5. Detection of antibodies against the huntingtin protein in human plasma

Author: Denis, Hélèna L., Alpaugh, Melanie, Alvarez, Claudia P., Fenyi, Alexis, Barker, Roger A., Chouinard, Sylvain, Arrowsmith, Cheryl H., Melki, Ronald, Labib, Richard, Harding, Rachel J., Cicchetti, Francesca, Cicchetti, Francesca [0000-0001-5490-1961], Apollo - University of Cambridge Repository, Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Structural Genomics Consortium, University of Toronto, Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), University of Cambridge [UK] (CAM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Princess Margaret Hospital, École Polytechnique de Montréal (EPM), Department of Pharmacology and Toxicology [Toronto], and ANR-17-JPCD-0002,TransPathND,Intraneuronal transport-related pathways across neurodegenerative diseases(2017)
Subjects: Pharmacology, Huntingtin Protein, [SDV]Life Sciences [q-bio], Neurodegenerative Diseases, Cell Biology, Antibodies, Plasma, Cellular and Molecular Neuroscience, Huntington Disease, Humans, Molecular Medicine, Original Article, Human samples, Molecular Biology, Huntington’s disease
Abstract: Funder: Huntington Society of Canada; doi: http://dx.doi.org/10.13039/100009836, Funder: NIHR BioResource; doi: http://dx.doi.org/10.13039/100017751, Funder: Huntington's Disease Society of America; doi: http://dx.doi.org/10.13039/100000887, Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder resulting from a CAG expansion in the huntingtin (HTT) gene, which leads to the production and accumulation of mutant huntingtin (mHTT). While primarily considered a disorder of the central nervous system, multiple changes have been described to occur throughout the body, including activation of the immune system. In other neurodegenerative disorders, activation of the immune system has been shown to include the production of antibodies against disease-associated pathological proteins. However, the existence of mHTT-targeted antibodies has never been reported. In this study, we assessed the presence and titer of antibodies recognizing HTT/mHTT in patients with HD (n = 66) and age- and gender-matched healthy controls (n = 66) using a combination of Western blotting and ELISA. Together, these analyses revealed that antibodies capable of recognizing HTT/mHTT were detectable in the plasma samples of all participants, including healthy controls. When antibody levels were monitored at different disease stages, it was observed that antibodies against full-length mHTT were highest in patients with severe disease while antibodies against HTTExon1 were elevated in patients with mild disease. Combined, these results suggest that antibodies detecting different forms of mHTT peak at different disease stages.
Published: 2023

6. DESIGN, SYNTHESIS AND CHARACTERISATION OF A NOVEL TYPE II B-RAF PARADOX BREAKER INHIBITOR

Author: Rohit Arora, Joannes T.M. Linders, Samia Aci-Sèche, Thomas Verheyen, Erika Van Heerde, Dirk Brehmer, Apirat Chaikuad, Stefan Knapp, Pascal Bonnet, Institut de Chimie Organique et Analytique (ICOA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Janssen Research and Development, Structural Genomics Consortium [Francfort, Allemagne], Buchmann Institute for Molecular Life Sciences [Francfort, Allemagne], and Goethe-Universität Frankfurt am Main-Goethe-Universität Frankfurt am Main
Subjects: Pharmacology, Organic Chemistry, Drug Discovery, General Medicine, [CHIM.THER]Chemical Sciences/Medicinal Chemistry
Abstract: International audience; The mutation V600E in B-Raf leads to MAPK pathway activation, uncontrolled cell proliferation, and tumorigenesis. ATP competitive type I B-Raf inhibitors, such as vemurafenib (1) and PLX4720 (4) efficiently block the MAPK pathways in B-Raf mutant cells, however these inhibitors induce conformational changes in the wild type B-Raf (wt B-Raf) kinase domain leading to heterodimerisation with C-Raf, causing paradoxical hyperactivation of the MAPK pathway. This unwanted activation may be avoided by another class of inhibitors (type II) which bind the kinase in the DFG-out conformation, such as AZ628 (3) preventing heterodimerization. Here we present a new B-Raf kinase domain inhibitor that represents a hybrid between 4 and 3. This novel inhibitor borrows the hinge binding region from 4 and the back pocket binding moiety from 3. We designed, synthesized, determined its binding mode, performed activity/selectivity studies, and molecular dynamics simulations in order to study the conformational effects induced by this inhibitor on wt and V600E mutant B-Raf kinase. We discovered that the inhibitor binds in a DFG-out/αC-helix-in conformation, did not induce the aforementioned paradoxical hyperactivation in the MAPK pathway, and it was active and highly selective for B-Raf. We propose that this merging approach can be used to design a novel class of B-Raf inhibitors for translational studies.
Published: 2023

7. New potent dual inhibitors of CK2 and Pim kinases: discovery and structural insights

Author: David S. Grierson, Panagis Filippakopoulos, Renaud Prudent, Céline F. Sautel, Jean-Claude Florent, Virginie Moucadel, Miriam López-Ramos, Claude Cochet, Stefan Knapp, Jean-Baptiste Reiser, Caroline Barette, Laurence Lafanechère, Frédéric Schmidt, Alex N. Bullock, Liliane Mouawad, Compartimentation et dynamique cellulaires (CDC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Imagerie intégrative de la molécule à l'organisme, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Transduction du signal : signalisation calcium, phosphorylation et inflammation, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Plateforme et Moyens Scientifiques et techniques communs / Centre de Criblage pour Molécules Bio-Actives (GPMS / CMBA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de physiologie cellulaire végétale (LPCV), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Nuffield Department of Clinical Medicine [Oxford], University of Oxford [Oxford], Department of Clinical Pharmacology, Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie structurale (IBS - UMR 5075), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Sciences et Techniques de la Ville - FR 2488 (IRSTV), Université d'Angers (UA)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-École nationale supérieure d'architecture de Nantes (ENSA Nantes)-La Rochelle Université (ULR)-Centre National de la Recherche Scientifique (CNRS), Genetics and Chemogenomics (GenChem), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), University of Oxford, Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Conception, synthèse et vectorisation de biomolécules (CSVB), Centre National de la Recherche Scientifique (CNRS), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Conception, synthèse et vectorisation de biomolécules. (CSVB), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris], Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC), Structural Genomics Consortium, Structural Genomics Consortium, University of Oxford, Biologie du Cancer et de l'Infection (BCI ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)
Subjects: MESH: Enzyme Stability, [SDV]Life Sciences [q-bio], MESH: Casein Kinase II, Crystallography, X-Ray, Biochemistry, Serine, 0302 clinical medicine, Enzyme Stability, Kinome, MESH: Animals, Enzyme Inhibitors, Casein Kinase II, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Tumor, Crystallography, Kinase, Proto-Oncogene Proteins c-pim-1, 3. Good health, MESH: Proto-Oncogene Proteins c-pim-1, MESH: Enzyme Inhibitors, 030220 oncology & carcinogenesis, Casein kinase 2, Biotechnology, MESH: Enzyme Activation, MESH: Cell Line, Tumor, High-throughput screening, Biology, chemistry, Cell Line, 03 medical and health sciences, Enzyme activator, Cell Line, Tumor, Genetics, [CHIM]Chemical Sciences, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein kinase A, Molecular Biology, antagonists and inhibitors, 030304 developmental biology, Binding Sites, MESH: Humans, MESH: Crystallography, X-Ray, Enzyme Activation, MESH: Binding Sites, drug effects, X-Ray, pharmacology, chemical synthesis
Abstract: International audience; Protein kinase casein kinase 2 (CK2) is a serine/threonine kinase with evidence of implication in growth dysregulation and apoptosis resistance, making it a relevant target for cancer therapy. Several CK2 inhibitors have been developed showing variable efficiency, emphasizing the need to expand the chemical diversity of those inhibitors. We report the identification and characterization of 2,8-difurandicarboxylic acid derivatives as a new class of nanomolar ATP-competitive inhibitors. Selectivity profiling pointed out proviral insertion Moloney virus kinases (Pim kinases) as the only other kinases that are significantly inhibited. By combining structure-activity relationship analysis with structural determination, we were able to determine the binding mode of these inhibitors for both kinases and to explain their strong inhibitory potency. Essential chemical features necessary for activity on both kinases were then identified. The described compounds are not cell permeable: however, they could provide a lead for developing novel inhibitors usable also in vivo. Given the similar but not redundant pathophysiological functions of CK2 and Pim family members, such inhibitors would provide new attractive leads for targeted cancer therapy. This work highlights that 2 functionally related kinases from different kinome branches display exquisite sensitivity to a common inhibitor.
Published: 2010

8. Structures of the cGMP-dependent protein kinase in malaria parasites reveal a unique structural relay mechanism for activation

Author: El Bakkouri, Majida, Kouidmi, Imène, Wernimont, Amy K., Amani, Mehrnaz, Hutchinson, Ashley, Loppnau, Peter, Kim, Jeong Joo, Flueck, Christian, Walker, John R., Seitova, Alma, Senisterra, Guillermo, Kakihara, Yoshito, Kim, Choel, Blackman, Michael J., Calmettes, Charles, Baker, David A., Hui, Raymond, University of Toronto, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Baylor College of Medicine (BCM), Baylor University, London School of Hygiene and Tropical Medicine (LSHTM), The Francis Crick Institute [London], Toronto General Hospital Research Institute [Canada] (TGHRI), The Structural Genomics Consortium is a registered charity (no. 1097737) that receives funds from AbbVie, Boehringer Ingelheim, the Canada Foundation for Innovation, the Canadian Institutes for Health Research, Genome Canada through the Ontario Genomics Institute (OGI-055), GlaxoSmithKline, Janssen, Lilly Canada, the Novartis Research Foundation, the Ontario Ministry of Economic Development and Innovation, Pfizer, Takeda, and the Wellcome Trust. This work was also supported by Wellcome Trust Grants 092809/Z/10/Z, 106240/Z/14/Z and 106239/Z/14/A (to D.A.B. and M.J.B.). This work was also supported by the Francis Crick Institute (M.J.B.) , which receives its core funding from Cancer Research UK Grant FC001043, UK Medical Research Council Grant FC001043, and Wellcome Trust Grant FC001043. C.C. is the recipient of Fonds de Recherche Québec–Santé (FRQS) Research Scholar Junior 1 Career Award 251848, supported by Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant RGPIN-2017-06091, Fonds de Recherche Québec–Nature et Technologies (FRQNT) Grant 2019-NC-253753, as well as with instrumentation and infrastructure support provided by the Armand–Frappier Foundation. This research used resources of the Canadian Light Source at Beamline 08ID-1, which is supported by the Canada Foundation for Innovation, Natural Sciences and Engineering Research Council of Canada, and Canadian Institutes of Health Research, and and of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract DE-AC02-06CH11357.
Subjects: Plasmodium, Medical Sciences, Binding Sites, Protein Conformation, [SDV]Life Sciences [q-bio], Plasmodium falciparum, malaria, Biological Sciences, Crystallography, X-Ray, Kinetics, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, PNAS Plus, cyclic GMP, Catalytic Domain, cardiovascular system, Cyclic GMP-Dependent Protein Kinases, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, structure, Amino Acid Sequence, signal transduction, Protein Binding
Abstract: Significance Despite being one of the first protein kinases discovered, cyclic guanosine-3′,5′-monophosphate (cGMP)-dependent protein kinase (PKG) has not been successfully crystallized previously, leaving many unanswered questions about its mechanism of activation. We report herein the structure of cGMP-free PKG from Plasmodium parasites, the causative agents of malaria, one of the world’s deadliest infectious diseases. The structures, combined with data from biochemical and biophysical experiments, provide insight into a mechanism of activation that involves previously unpredicted interdomain communication via a structural relay system. In addition to the full structure of PKG, our work contributes important functional information for a key antimalarial drug target., The cyclic guanosine-3′,5′-monophosphate (cGMP)-dependent protein kinase (PKG) was identified >25 y ago; however, efforts to obtain a structure of the entire PKG enzyme or catalytic domain from any species have failed. In malaria parasites, cooperative activation of PKG triggers crucial developmental transitions throughout the complex life cycle. We have determined the cGMP-free crystallographic structures of PKG from Plasmodium falciparum and Plasmodium vivax, revealing how key structural components, including an N-terminal autoinhibitory segment (AIS), four predicted cyclic nucleotide-binding domains (CNBs), and a kinase domain (KD), are arranged when the enzyme is inactive. The four CNBs and the KD are in a pentagonal configuration, with the AIS docked in the substrate site of the KD in a swapped-domain dimeric arrangement. We show that although the protein is predominantly a monomer (the dimer is unlikely to be representative of the physiological form), the binding of the AIS is necessary to keep Plasmodium PKG inactive. A major feature is a helix serving the dual role of the N-terminal helix of the KD as well as the capping helix of the neighboring CNB. A network of connecting helices between neighboring CNBs contributes to maintaining the kinase in its inactive conformation. We propose a scheme in which cooperative binding of cGMP, beginning at the CNB closest to the KD, transmits conformational changes around the pentagonal molecule in a structural relay mechanism, enabling PKG to orchestrate rapid, highly regulated developmental switches in response to dynamic modulation of cGMP levels in the parasite.
Published: 2019

9. A Tail-Based Mechanism Drives Nucleosome Demethylation by the LSD2/NPAC Multimeric Complex

Author: Sarah Picaud, Chiara Marabelli, Andrea Mattevi, Sara Marchese, Giuseppe Ciossani, Biagina Marrocco, Guy Schoehn, Sriram Subramaniam, Panagis Filippakopoulos, Sagar Chittori, Daniela Rhodes, Federico Forneris, Simona Pilotto, Department of Biology and Biotechnology, University of Pavia, Genetics Branch [Bethesda, MD, USA] (Center for Cancer Research), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Structural Genomics Consortium, University of Oxford [Oxford], Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institute of Structural Biology, The University of British Columbia, Platefome de Microscopie électronique IBS/ISBG, ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), ANR-10-LABX-0004,CeMEB,Mediterranean Center for Environment and Biodiversity(2010), Università degli Studi di Pavia = University of Pavia (UNIPV), University of Oxford, Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Nanyang Technological University [Singapour], School of Biological Sciences, Lee Kong Chian School of Medicine (LKCMedicine), and NTU Institute of Structural Biology
Subjects: 0301 basic medicine, Models, Molecular, Enzyme complex, cryoelectron microscopy, Chromatin silencing, General Biochemistry, Genetics and Molecular Biology, chromatin reader, Histones, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Histone demethylation, Protein Domains, RNA polymerase, flavoenzyme, Nucleosome, Humans, Amino Acid Sequence, lcsh:QH301-705.5, Histone Demethylases, Histone Demethylation, biology, epigenetics, histone demethylation, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Chemistry, Cryoelectron Microscopy, Nuclear Proteins, Multifunctional Enzymes, Science::Biological sciences [DRNTU], Cell biology, Demethylation, Nucleosomes, 030104 developmental biology, lcsh:Biology (General), evolution of protein function, biology.protein, Demethylase, molecular recognition, Oxidoreductases, 030217 neurology & neurosurgery, DNA
Abstract: Summary: LSD1 and LSD2 are homologous histone demethylases with opposite biological outcomes related to chromatin silencing and transcription elongation, respectively. Unlike LSD1, LSD2 nucleosome-demethylase activity relies on a specific linker peptide from the multidomain protein NPAC. We used single-particle cryoelectron microscopy (cryo-EM), in combination with kinetic and mutational analysis, to analyze the mechanisms underlying the function of the human LSD2/NPAC-linker/nucleosome complex. Weak interactions between LSD2 and DNA enable multiple binding modes for the association of the demethylase to the nucleosome. The demethylase thereby captures mono- and dimethyl Lys4 of the H3 tail to afford histone demethylation. Our studies also establish that the dehydrogenase domain of NPAC serves as a catalytically inert oligomerization module. While LSD1/CoREST forms a nucleosome docking platform at silenced gene promoters, LSD2/NPAC is a multifunctional enzyme complex with flexible linkers, tailored for rapid chromatin modification, in conjunction with the advance of the RNA polymerase on actively transcribed genes. : Through biophysical, biochemical, and structural studies, including cryo-EM, Marabelli et al. describe how NPAC promotes LSD2 productive interaction with the nucleosome in a rapid and flexible manner. Their findings provide a molecular mechanism for LSD2 activity in the context of H3K4me2 demethylation during Pol II transcriptional elongation. Keywords: histone demethylation, cryoelectron microscopy, chromatin reader, flavoenzyme, epigenetics, evolution of protein function, molecular recognition
Published: 2019

10. New pyrido[3,4-g]quinazoline derivatives as CLK1 and DYRK1A inhibitors: synthesis, biological evaluation and binding mode analysis

Author: Yannick J. Esvan, Pascale Moreau, Andreas C. Joerger, Fabrice Anizon, Helmi Tazarki, Stéphane Bach, Martin Schröder, Blandine Baratte, Deep Chatterjee, Wael Zeinyeh, Jameleddine Khiari, Béatrice Josselin, Sandrine Ruchaud, Francis Giraud, Stefan Knapp, Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Clermont-Ferrand (ICCF), SIGMA Clermont (SIGMA Clermont)-Institut de Chimie du CNRS (INC)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Institut Supérieur de l'Enseignement et de la Formation Continue [Tunis] (ISEFC), Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Buchmann Institute for Molecular Life Sciences and Structural Genomics Consortium (SGC), Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Plate-forme de criblage d'inhibiteurs de protéines kinases=Kinase Inhibitor Specialized Screening facility (KISSf), Fédération de recherche de Roscoff (FR2424), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Intégrative (LBI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Université Clermont Auvergne (UCA)
Subjects: DYRK1A, Protein Conformation, [SDV]Life Sciences [q-bio], CLK1, Chemistry Techniques, Synthetic, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Protein Serine-Threonine Kinases, 01 natural sciences, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Cell Line, Tumor, Drug Discovery, Quinazoline, Humans, [CHIM]Chemical Sciences, Viability assay, Tyrosine, DYRKA, Protein Kinase Inhibitors, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Pharmacology, 0303 health sciences, CLK1, DYRKA, Kinase inhibitors, Pyridoquinazolines, 010405 organic chemistry, Kinase, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Cyclin-dependent kinase 5, Organic Chemistry, Pyridoquinazolines, General Medicine, Protein-Tyrosine Kinases, 3. Good health, 0104 chemical sciences, Molecular Docking Simulation, chemistry, Biochemistry, Kinase inhibitors, Drug Design, Quinazolines, Casein kinase 1, Protein Binding
Abstract: International audience; Cdc2-like kinase 1 (CLK1) and dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) are involved in the regulation of alternative pre-mRNA splicing. Dysregulation of this process has been linked to cancer progression and neurodegenerative diseases, making CLK1 and DYRK1A important therapeutic targets. Here we describe the synthesis of new pyrido[3,4-g]quinazoline derivatives and the evaluation of the inhibitory potencies of these compounds toward CDK5, CK1, GSK3, CLK1 and DYRK1A. Introduction of aminoalkylamino groups at the 2-position resulted in several compounds with low nanomolar affinity and selective inhibition of CLK1 and/or DYRK1A. Their evaluation on several immortalized or cancerous cell lines showed varying degree of cell viability reduction. Co-crystal structures of CLK1 with two of the most potent compounds revealed two alternative binding modes of the pyrido[3,4-g]quinazoline scaffold that can be exploited for future inhibitor design.
Published: 2019

11. Nut Directs p300-Dependent, Genome-Wide H4 Hyperacetylation in Male Germ Cells

Author: Shiota, H, Barral, S, Buchou, T, Tan, M, Couté, Y, Charbonnier, G, Reynoird, N, Boussouar, F, Gérard, M, Zhu, M, Bargier, L, Puthier, D, Chuffart, F, Bourova-Flin, E, Picaud, S, Filippakopoulos, P, Goudarzi, A, Ibrahim, Z, Panne, D, Rousseaux, S, Zhao, Y, Khochbin, S, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Shanghai Institute of Materia Medica, Chinese Academy of Sciences [Changchun Branch] (CAS), Etude de la dynamique des protéomes (EDyP ), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche du CEA/DSV/iBiTec-S/SIMOPRO, Structural Genomics Consortium, University of Oxford, European Molecular Biology Laboratory [Grenoble] (EMBL), Ben May Department of Cancer Research, The University of Chicago Medicine, ANR-15-IDEX-0002,UGA,IDEX UGA(2015), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), European Project: 289880,EC:FP7:PEOPLE,FP7-PEOPLE-2011-ITN,REPRO-TRAIN(2012), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Etude de la dynamique des protéomes (EDyP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Interactions et dynamique des environnements de surface (IDES), Université Paris-Sud - Paris 11 (UP11)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de l'Informatique du Parallélisme (LIP), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), University of Oxford [Oxford], Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire [Grenoble] (CHU)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])
Subjects: Male, Midline, Xenopus, [SDV]Life Sciences [q-bio], Carcinoma Cells, Protamine, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Histones, Mice, Animals, p300-CBP Transcription Factors, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Spermatogenesis, lcsh:QH301-705.5, Infertility, Male, ComputingMilieux_MISCELLANEOUS, Nut, Genome, digestive, oral, and skin physiology, Nuclear Proteins, food and beverages, Acetylation, Spermatozoa, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Neoplasm Proteins, Histone Code, lcsh:Biology (General), Protein Processing, Post-Translational, Protein Binding
Abstract: International audience; Graphical Abstract Highlights d Nut is a post-meiotically expressed gene that is critical for male fertility d Nut recruits p300 and/or CBP to enhance histone H4K5 and H4K8 acetylation d Nut-mediated histone hyperacetylation is required for histone-to-protamine transition A transcription-independent histone hyperacetylation is associated with near-total histone replacement during mouse spermatogenesis. Shiota et al. show the oncogenic factor Nut is expressed in post-meiotic male germ cells, where it recruits p300 and/or CBP and enhances histone H4K5 and H4K8 acetylation, leading to histone-to-protamine replacement.Nuclear protein in testis (Nut) is a universal oncogenic driver in the highly aggressive NUT midline carcinoma, whose physiological function in male germ cells has been unclear. Here we show that expression of Nut is normally restricted to post-meiotic spermatogenic cells, where its presence triggers p300-dependent genome-wide histone H4 hyper-acetylation, which is essential for the completion of histone-to-protamine exchange. Accordingly, theinactivation of Nut induces male sterility with spermatogenesis arrest at the histone-removal stage. Nut uses p300 and/or CBP to enhance acetylation of H4 at both K5 and K8, providing binding sites for the first bromodomain of Brdt, the testis-specific member of the BET family, which subsequently mediates genome-wide histone removal. Altogether, our data reveal the detailed molecular basis of the global histone hyperacetylation wave, which occurs before the final compaction of the male genome.
Published: 2018

12. Hepatitis Delta Virus histone mimicry drives the recruitment of chromatin remodelers for viral RNA replication

Author: Abeywickrama-Samarakoon, Natali, Cortay, Jean-Claude, Sureau, Camille, Müller, Susanne, Alfaiate, Dulce, Guerrieri, Francesca, Chaikuad, Apirat, Schröder, Martin, Merle, Philippe, Levrero, Massimo, Dény, Paul, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Virologie Moléculaire [Paris], Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Structural Genomics Consortium [Francfort, Allemagne], Buchmann Institute for Molecular Life Sciences [Francfort, Allemagne], Goethe-Universität Frankfurt am Main-Goethe-Universität Frankfurt am Main, Département de Pathologie et Immunologie [Genève, Suisse], Université de Genève (UNIGE), Service de Maladies Infectieuses et Tropicales [Hôpital de la Croix-Rousse - HCL], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Center for Life NanoScience [Rome, Italie] (CLNS), Italian Institute of Technology [Rome, Italie] (IIT), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Service d'Hépatologie [Hôpital de la Croix-Rousse - HCL], Laboratoire de Microbiologie Clinique [Bobigny], Groupe des Hôpitaux Universitaires de Paris - Seine-Saint-Denis [Bobigny], Université Paris 13 (UP13)-UFR Santé, Médecine et Biologie Humaine-Université Paris 13 (UP13)-UFR Santé, Médecine et Biologie Humaine, P.D. was supported by an INSERM Interface Contract (2007–2011). N.A.S. was the recipient of a PhD grant from the French Ministry of Research and Technology (2013–2016) and a fellowship from the ANR@RACTION (2017–2018). This work was supported by grants from the Agence Nationale pour la Recherche sur le SIDA et les hépatites virales (ANRS) to P.D. (AO 2011–1 and AO 2013–1) and to M.L. (numbers ECTZ8323, ECTZ27696, ECTZ66014), from the Agence Nationale de la Recherche (ANR@TRACTION) to M.L., from the EU project 667273 HEP-CAR to M.L. S.M.K., A.P. and M.S. are supported by the SGC, a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant no. 115766], Janssen, Merck KGaA Darmstadt Germany, MSD, Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation-FAPESP, Takeda, and Wellcome [106169/ZZ14/Z]., European Project: 667273,H2020,H2020-PHC-2015-two-stage,HEP-CAR(2016), Bodescot, Myriam, Mechanisms underlying hepatocellular carcinoma pathogenesis and impact of co-morbidities. - HEP-CAR - - H20202016-01-01 - 2019-12-31 - 667273 - VALID, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Université de Genève = University of Geneva (UNIGE), and Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA)
Subjects: Hepatitis B virus, Science, viruses, Pathogenesis, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Virus Replication, Microbiology, Article, Cell Line, Histones, Protein Domains, Humans, ddc:610, RNA, Small Interfering, lcsh:Science, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Hepatitis delta Antigens, Molecular Mimicry, virus diseases, Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, biochemical phenomena, metabolism, and nutrition, Chromatin Assembly and Disassembly, Gene Knockdown Techniques, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, RNA, Viral, lcsh:Q, RNA Polymerase II, Hepatitis Delta Virus, Transcription Factors, General
Abstract: Hepatitis Delta virus (HDV) is a satellite of Hepatitis B virus with a single-stranded circular RNA genome. HDV RNA genome synthesis is carried out in infected cells by cellular RNA polymerases with the assistance of the small hepatitis delta antigen (S-HDAg). Here we show that S-HDAg binds the bromodomain (BRD) adjacent to zinc finger domain 2B (BAZ2B) protein, a regulatory subunit of BAZ2B-associated remodeling factor (BRF) ISWI chromatin remodeling complexes. shRNA-mediated silencing of BAZ2B or its inactivation with the BAZ2B BRD inhibitor GSK2801 impairs HDV replication in HDV-infected human hepatocytes. S-HDAg contains a short linear interacting motif (SLiM) KacXXR, similar to the one recognized by BAZ2B BRD in histone H3. We found that the integrity of the S-HDAg SLiM sequence is required for S-HDAg interaction with BAZ2B BRD and for HDV RNA replication. Our results suggest that S-HDAg uses a histone mimicry strategy to co-activate the RNA polymerase II-dependent synthesis of HDV RNA and sustain HDV replication., Histone mimicry of viral components is a strategy to subvert host factors for virus replication. Here, the authors show that an acetylated histone-like motif of the small Hepatitis Delta Antigen (S-HDAg) interacts with the chromatin remodeler BAZ2B to recruit the DNA-dependent RNA polymerase II for HDV RNA replication.
Published: 2018

13. Gaia Data Release 1: Testing parallaxes with local Cepheids and RR Lyrae stars

Author: Gaia Collaboration, Clementini, G., Eyer, L., Ripepi, V., Marconi, M., Muraveva, T., Garofalo, A., Sarro, L. M., Palmer, M., Luri, X., Molinaro, R., Rimoldini, L., Szabados, L., Musella, I., Anderson, R. I., Prusti, T., Bruijne, J. H. J., Brown, A. G. A., Vallenari, A., Babusiaux, C., Bailer-Jones, C. A. L., Bastian, U., Biermann, M., Evans, D. W., Jansen, F., Jordi, C., Klioner, S. A., Lammers, U., Lindegren, L., Mignard, F., Panem, C., Pourbaix, D., Randich, S., Sartoretti, P., Siddiqui, H. I., Soubiran, C., Valette, V., Leeuwen, F., Walton, N. A., Aerts, C., Arenou, F., Cropper, M., Drimmel, R., Høg, E., Katz, D., Lattanzi, M. G., O Mullane, W., Grebel, E. K., Holland, A. D., Huc, C., Passot, X., Perryman, M., Bramante, L., Cacciari, C., Castañeda, J., Chaoul, L., Cheek, N., Angeli, F., Fabricius, C., Guerra, R., Hernández, J., Jean-Azntoine-Piccolo, A., Masana, E., Messineo, R., Mowlavi, N., Nienartowicz, K., Ordóñez-Blanco, D., Panuzzo, P., Portell, J., Richards, P. J., Riello, M., Seabroke, G. M., Tanga, P., Thévenin, F., Torra, J., Els, S. G., Gracia-Abril, G., Comoretto, G., Garcia-Reinaldos, M., Lock, T., Mercier, E., Altmann, M., Andrae, R., Astraatmadja, T. L., Bellas-Velidis, I., Benson, K., Berthier, J., Blomme, R., Busso, G., Carry, B., Cellino, A., Cowell, S., Creevey, O., Cuypers, J., Davidson, M., Ridder, J., Torres, A., Delchambre, L., Oro, A., Ducourant, C., Frémat, Y., García-Torres, M., Gosset, E., Halbwachs, J. -L, Hambly, N. C., Harrison, D. L., Hauser, M., Hestroffer, D., Hodgkin, S. T., Huckle, H. E., Hutton, A., Jasniewicz, G., Jordan, S., Kontizas, M., Korn, A. J., Lanzafame, A. C., Manteiga, M., Moitinho, A., Muinonen, K., Osinde, J., Pancino, E., Pauwels, T., Petit, J. -M, Recio-Blanco, A., Robin, A. C., Siopis, C., Smith, M., Smith, K. W., Sozzetti, A., Thuillot, W., Reeven, W., Viala, Y., Abbas, U., Abreu Aramburu, A., Accart, S., Aguado, J. J., Allan, P. M., Allasia, W., Altavilla, G., Álvarez, M. A., Alves, J., Andrei, A. H., Anglada Varela, E., Antiche, E., Antoja, T., Antón, S., Arcay, B., Bach, N., Baker, S. G., Balaguer-Núñez, L., Barache, C., Barata, C., Barbier, A., Barblan, F., Barrado Y Navascués, D., Barros, M., Barstow, M. A., Becciani, U., Bellazzini, M., Bello García, A., Belokurov, V., Bendjoya, P., Berihuete, A., Bianchi, L., Bienaymé, O., Billebaud, F., Blagorodnova, N., Blanco-Cuaresma, S., Boch, T., Bombrun, A., Borrachero, R., Bouquillon, S., Bourda, G., Bouy, H., Bragaglia, A., Breddels, M. A., Brouillet, N., Brüsemeister, T., Bucciarelli, B., Burgess, P., Burgon, R., Burlacu, A., Busonero, D., Buzzi, R., Caffau, E., Cambras, J., Campbell, H., Cancelliere, R., Cantat-Gaudin, T., Carlucci, T., Carrasco, J. M., Castellani, M., Charlot, P., Charnas, J., Chiavassa, A., Clotet, M., Cocozza, G., Collins, R. S., Costigan, G., Crifo, F., Cross, N. J. G., Crosta, M., Crowley, C., Dafonte, C., Damerdji, Y., Dapergolas, A., David, P., David, M., Cat, P., Felice, F., Laverny, P., Luise, F., March, R., Souza, R., Debosscher, J., Del Pozo, E., Delbo, M., Delgado, A., Delgado, H. E., Di Matteo, P., Diakite, S., Distefano, E., Dolding, C., Dos Anjos, S., Drazinos, P., Durán, J., Dzigan, Y., Edvardsson, B., Enke, H., Evans, N. W., Eynard Bontemps, G., Fabre, C., Fabrizio, M., Faigler, S., Falcão, A. J., Farràs Casas, M., Federici, L., Fedorets, G., Fernández-Hernánde, J., Fernique, P., Fienga, A., Figueras, F., Filippi, F., Findeisen, K., Fonti, A., Fouesneau, M., Fraile, E., Fraser, M., Fuchs, J., Gai, M., Galleti, S., Galluccio, L., Garabato, D., García-Sedano, F., Garralda, N., Gavras, P., Gerssen, J., Geyer, R., Gilmore, G., Girona, S., Giuffrida, G., Gomes, M., González-Marcos, A., González-Núñez, J., González-Vidal, J. J., Granvik, M., Guerrier, A., Guillout, P., Guiraud, J., Gúrpide, A., Gutiérrez-Sánchez, R., Guy, L. P., Haigron, R., Hatzidimitriou, D., Haywood, M., Heiter, U., Helmi, A., Hobbs, D., Hofmann, W., Holl, B., Holland, G., Hunt, J. A. S., Hypki, A., Icardi, V., Irwin, M., Jevardat Fombelle, G., Jofré, P., Jonker, P. G., Jorissen, A., Julbe, F., Karampelas, A., Kochoska, A., Kohley, R., Kolenberg, K., Kontizas, E., Koposov, S. E., Kordopatis, G., Koubsky, P., Krone-Martins, A., Kudryashova, M., Kull, I., Bachchan, R. K., Lacoste-Seris, F., Lanza, A. F., Lavigne, J. -B, Le Poncin-Lafitte, C., Lebreton, Y., Lebzelter, T., Leccia, S., Leclerc, N., Lecoeur-Taibi, I., Lemaitre, V., Lenhardt, H., Leroux, F., Liao, S., Licata, E., Lindstrøm, H. E. P., Lister, T. A., Livanou, E., Lobel, A., Löffler, W., López, M., Lorenz, D., Macdonald, I., Magalhães Fernandes, T., Managau, S., Mann, R. G., Mantelet, G., Marchal, O., Marchant, J. M., Marinoni, S., Marrese, P. M., Marschalkó, G., Marshall, D. J., Martín-Fleitas, J. M., Martino, M., Mary, N., Matijevič, G., Mazeh, T., Mcmillan, P. J., Messina, S., Michalik, D., Millar, N. R., Miranda, B. M. H., Molina, D., Molinaro, M., Molnár, L., Moniez, M., Montegriffo, P., Mor, R., Mora, A., Morbidelli, R., Morel, T., Morgenthaler, S., Morris, D., Mulone, A. F., Narbonne, J., Nelemans, G., Nicastro, L., Noval, L., Ordénovic, C., Ordieres-Meré, J., Osborne, P., Pagani, C., Pagano, I., Pailler, F., Palacin, H., Palaversa, L., Parsons, P., Pecoraro, M., Pedrosa, R., Pentikäinen, H., Pichon, B., Piersimoni, A. M., Pineau, F. -X, Plachy, E., Plum, G., Poujoulet, E., Prša, A., Pulone, L., Ragaini, S., Rago, S., Rambaux, N., Ramos-Lerate, M., Ranalli, P., Rauw, G., Read, A., Regibo, S., Reylé, C., Ribeiro, R. A., Riva, A., Rixon, G., Roelens, M., Romero-Gómez, M., Rowell, N., Royer, F., Ruiz-Dern, L., Sadowski, G., Sagristà Sellés, T., Johannes Sahlmann, Salgado, J., Salguero, E., Sarasso, M., Savietto, H., Schultheis, M., Sciacca, E., Segol, M., Segovia, J. C., Segransan, D., Shih, I-C, Smareglia, R., Smart, R. L., Solano, E., Solitro, F., Sordo, R., Soria Nieto, S., Souchay, J., Spagna, A., Spoto, F., Stampa, U., Steele, I. A., Steidelmüller, H., Stephenson, C. A., Stoev, H., Suess, F. F., Süveges, M., Surdej, J., Szegedi-Elek, E., Tapiador, D., Taris, F., Tauran, G., Taylor, M. B., Teixeira, R., Terrett, D., Tingley, B., Trager, S. C., Turon, C., Ulla, A., Utrilla, E., Valentini, G., Elteren, A., Hemelryck, E., Leeuwen, M., Varadi, M., Vecchiato, A., Veljanoski, J., Via, T., Vicente, D., Vogt, S., Voss, H., Votruba, V., Voutsinas, S., Walmsley, G., Weiler, M., Weingrill, K., Wevers, T., Wyrzykowski, Ł., Yoldas, A., Žerjal, M., Zucker, S., Zurbach, C., Zwitter, T., Alecu, A., Allen, M., Allende Prieto, C., Amorim, A., Anglada-Escudé, G., Arsenijevic, V., Azaz, S., Balm, P., Beck, M., Bernstein, H. -H, Bigot, L., Bijaoui, A., Blasco, C., Bonfigli, M., Bono, G., Boudreault, S., Bressan, A., Brown, S., Brunet, P. -M, Bunclark, P., Buonanno, R., Butkevich, A. G., Carret, C., Carrion, C., Chemin, L., Chéreau, F., Corcione, L., Darmigny, E., Boer, K. S., Teodoro, P., Zeeuw, P. T., Delle Luche, C., Domingues, C. D., Dubath, P., Fodor, F., Frézouls, B., Fries, A., Fustes, D., Fyfe, D., Gallardo, E., Gallegos, J., Gardiol, D., Gebran, M., Gomboc, A., Gómez, A., Grux, E., Gueguen, A., Heyrovsky, A., Hoar, J., Iannicola, G., Isasi Parache, Y., Janotto, A. -M, Joliet, E., Jonckheere, A., Keil, R., Kim, D. -W, Klagyivik, P., Klar, J., Knude, J., Kochukhov, O., Kolka, I., Kos, J., Kutka, A., Lainey, V., Lebouquin, D., Liu, C., Loreggia, D., Makarov, V. V., Marseille, M. G., Martayan, C., Martinez-Rubi, O., Massart, B., Meynadier, F., Mignot, S., Munari, U., Nguyen, A. -T, Nordlander, T., O Flaherty, K. S., Ocvirk, P., Olias Sanz, A., Ortiz, P., Osorio, J., Oszkiewicz, D., Ouzounis, A., Park, P., Pasquato, E., Peltzer, C., Peralta, J., Péturaud, F., Pieniluoma, T., Pigozzi, E., Poels, J., Prat, G., Prod Homme, T., Raison, F., Rebordao, J. M., Risquez, D., Rocca-Volmerange, B., Rosen, S., Ruiz-Fuertes, M. I., Russo, F., Sembay, S., Serraller Vizcaino, I., Short, A., Siebert, A., Silva, H., Sinachopoulos, D., Slezak, E., Soffel, M., Sosnowska, D., Straižys, V., Ter Linden, M., Terrell, D., Theil, S., Tiede, C., Troisi, L., Tsalmantza, P., Tur, D., Vaccari, M., Vachier, F., Valles, P., Hamme, W., Veltz, L., Virtanen, J., Wallut, J. -M, Wichmann, R., Wilkinson, M. I., Ziaeepour, H., Zschocke, S., INAF - Osservatorio Astronomico di Bologna (OABO), Istituto Nazionale di Astrofisica (INAF), Geneva Observatory, University of Geneva [Switzerland], INAF - Osservatorio Astronomico di Capodimonte (OAC), Dipartimento di Fisica e Astronomia [Bologna], Università di Bologna [Bologna] (UNIBO), Departamento de Inteligencia Artificial [UPM, Spain] (DIA), Universidad Politécnica de Madrid (UPM), Institut de Ciencies del Cosmos (ICCUB), Universitat de Barcelona (UB), Istituto Nazionale di Astrofisica (Istituto Nazionale di Astrofisica), Istituto Nazionale di Fisica Nucleare (INFN), Konkoly Observatory, Research Centre for Astronomy and Earth Sciences [Budapest], Hungarian Academy of Sciences (MTA)-Hungarian Academy of Sciences (MTA), University of California [Santa Cruz] (UCSC), University of California, Gastroenterology and Hepatology, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), University of Manchester, Galaxies, Etoiles, Physique, Instrumentation (GEPI), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Aberystwyth University, Agence Spatiale Européenne (ESA), European Space Agency (ESA), Joseph Louis LAGRANGE (LAGRANGE), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Observatoire de la Côte d'Azur, COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Human Cancer Genetics Program, Comprehensive Cancer Center-College of Medicine and Public Health [Colombus], Centre National d'Études Spatiales [Toulouse] (CNES), Instituut voor Sterrenkunde [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of Illinois at Urbana Champaign (UIUC), University of Illinois at Urbana-Champaign [Urbana], University of Illinois System-University of Illinois System, The Open University [Milton Keynes] (OU), Department of Biomedical, Metabolic and Neural Sciences [Modena], University of Las Palmas de Gran Canaria (ULPGC), Université de Montpellier (UM), Departament de Geodinamica i Geofısica, Facultat de Geologia, Astrophysique Interprétation Modélisation (AIM (UMR_7158 / UMR_E_9005 / UM_112)), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), European Space Astronomy Centre (ESAC), Professions, institutions, temporalités (PRINTEMPS), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Planétologie et Géodynamique [UMR 6112] (LPG), Université d'Angers (UA)-Université de Nantes - Faculté des Sciences et des Techniques, Université de Nantes (UN)-Université de Nantes (UN)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Systèmes de Référence Temps Espace (SYRTE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), National Institute for Subatomic Physics Nikhef [Amsterdam] (NIKHEF), Mullard Space Science Laboratory (MSSL), University College of London [London] (UCL), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Mécanique Céleste et de Calcul des Ephémérides (IMCCE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Royal Observatory of Belgium [Brussels] (ROB), Open University of Israël, M2A 2017, Laboratoire d'Astrophysique de Bordeaux [Pessac] (LAB), Université de Bordeaux (UB)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Picardie Jules Verne (UPJV), Laboratoire Univers et Particules de Montpellier (LUPM), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Department of Pathology and Cell Biology, Columbia University [New York], Department of Physics and Astronomy [Uppsala], Uppsala University, INAF - Osservatorio Astrofisico di Catania (OACT), Finnish Geospatial Research Institute (FGI), Helsinki Institute of Physics (HIP), University of Helsinki, Univers, Transport, Interfaces, Nanostructures, Atmosphère et environnement, Molécules (UMR 6213) (UTINAM), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), NASA Goddard Space Flight Center (GSFC), AUTRES, École Centrale de Nantes (ECN), University of Cambridge [UK] (CAM), EURIX (.), Fundaçao Cearense de Meteorologia e Recursos Hidricos, ARHEOINVEST, Universitatea Alexandru Ioan Cuza [Lasi], Institut d'écologie et des sciences de l'environnement de Paris (IEES), Institut National de la Recherche Agronomique (INRA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Department of Medicine, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department of Environmental Chemistry, IDAEA-CSIC, Institute of Environmental Assessment and Water Research (IDAEA), Consejo Superior de Investigaciones Científicas [Spain] (CSIC)-Consejo Superior de Investigaciones Científicas [Spain] (CSIC), Institut de Planétologie et d'Astrophysique de Grenoble (IPAG), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Observatoire des Sciences de l'Univers de Grenoble (OSUG ), Institut polytechnique de Grenoble - Grenoble Institute of Technology [2007-2019] (Grenoble INP [2007-2019])-Institut national des sciences de l'Univers (INSU - CNRS)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology [2007-2019] (Grenoble INP [2007-2019])-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Department of Physics and Astronomy [Leicester], University of Leicester, ASP 2017, FORMATION STELLAIRE 2017, Atotech Deutschland GmbH, Atotech, University of New South Wales [Sydney] (UNSW), Centre d'étude spatiale des rayonnements (CESR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Centre National d'Études Spatiales [Toulouse] (CNES)-Météo France-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Météo France, Observatoire de Haute-Provence (OHP), Institut Pythéas (OSU PYTHEAS), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut de Recherche pour le Développement (IRD), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institute of Astronomy [Leuven], Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Computing, Electronics and Mechatronics, Universidad de las Américas [Puebla] (UDLAP), Swansea University, Cognition, Langues, Langage, Ergonomie (CLLE-ERSS), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Toulouse - Jean Jaurès (UT2J)-Université Bordeaux Montaigne-Centre National de la Recherche Scientifique (CNRS), Scuola Internazionale Superiore di Studi Avanzati / International School for Advanced Studies (SISSA / ISAS), Computational Intelligence Research Group (CA3), Centre of Technology and Systems (CTS), Faculty of Sciences and Technology (FCT NOVA), Universidade Nova de Lisboa = NOVA University of Lisboa (NOVA)-Universidade Nova de Lisboa = NOVA University of Lisboa (NOVA)-Faculty of Sciences and Technology (FCT NOVA), Universidade Nova de Lisboa = NOVA University of Lisboa (NOVA)-Universidade Nova de Lisboa = NOVA University of Lisboa (NOVA)-Faculdade de Ciências e Tecnologia (FCT NOVA), Universidade Nova de Lisboa = NOVA University of Lisboa (NOVA), Géoazur (GEOAZUR 7329), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de la Côte d'Azur, COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Université Côte d'Azur (UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Università degli Studi di Roma 'La Sapienza' [Rome], Laboratoire pour l'utilisation des lasers intenses (LULI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Astrometry, INAF - Osservatorio Astrofisico di Torino (OATo), Istituto Nazionale di Astrofisica (INAF)-Istituto Nazionale di Astrofisica (INAF), Universidade de Lisboa (ULISBOA), Department of Mechanical, Informatics and Aerospace Engineering [León], Universidad de León [León], Observatoire astronomique de Strasbourg (ObAS), Université de Strasbourg (UNISTRA)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Sciences Pour l'Oenologie (SPO), Institut National de la Recherche Agronomique (INRA)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut de Recherche pour le Développement (IRD [Nouvelle-Calédonie])-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Sciences Po Paris - Institut d'études politiques de Paris (IEP Paris), Laboratory of the Institute for Fiscal Studies (IFS), Institute for Fiscal Studies, Department of Physics [Athens], National and Kapodistrian University of Athens = University of Athens (NKUA | UoA), Department of Food & Nutritional Sciences, University of Reading (UOR), Heckscher-Klinikum, Northeast Structural Genomics Consortium, Department of Biological Sciences, Columbia University, New York, New York, USA., SRON Netherlands Institute for Space Research (SRON), Institut d'Astronomie et d'Astrophysique, Université libre de Bruxelles (ULB), Virulence bactérienne et maladies infectieuses (VBMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Thérapeutiques cliniques et expérimentales des infections (EA 3826) (EA 3826), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de bactériologie et hygiène hospitalière [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire national de métrologie et d'essais - Systèmes de Référence Temps-Espace (LNE - SYRTE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Institut de Physique de Rennes (IPR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Chinese Academy of Sciences [Beijing] (CAS), Atmel Corporation (ATMEL), ATMEL, Astrophysics Research Institute [Liverpool] (ARI), Liverpool John Moores University (LJMU), Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Matériaux, ingénierie et science [Villeurbanne] (MATEIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche sur la Fusion par confinement Magnétique (IRFM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), INAF - Osservatorio Astronomico di Trieste (OAT), Laboratoire SUBATECH Nantes (SUBATECH), Mines Nantes (Mines Nantes)-Université de Nantes (UN)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de l'Accélérateur Linéaire (LAL), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Universidad de Granada (UGR), RedZinc Services Ltd.[Dublin], Laboratoire de Physico -& Toxico Chimie des systèmes naturels (LPTC), Université Sciences et Technologies - Bordeaux 1-Centre National de la Recherche Scientifique (CNRS), Centre Atlantique de Philosophie (CAPHI), PRES Université Nantes Angers Le Mans (UNAM), GIRM, Instituto Politécnico de Leiria, Institut de Physique et Chimie des Matériaux de Strasbourg (IPCMS), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, National Observatory of Athens, Institute for Space Applications and Remote Sensing, Lund Observatory, Lund University [Lund], Laboratoire de Chimie, Catalyse, Polymères et Procédés, R 5265 (C2P2), Centre National de la Recherche Scientifique (CNRS)-École supérieure de Chimie Physique Electronique de Lyon (CPE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institut de recherche de l'European Business School (IREBS), European Business School Paris (EBS Paris), Département Réseaux, Information, Multimédia (RIM-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Centre G2I, Department of Biochemical and Chemical Engineering, Technische Universität Dortmund [Dortmund] (TU), Équipes de Recherches Interlangues : Mémoires, Identités, Territoires (ERIMIT), Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université Panthéon-Sorbonne - UFR d'Économie (UP1 UFR02), Université Panthéon-Sorbonne (UP1), Observatoire Astronomique de l'Université de Genève (ObsGE), Université de Genève (UNIGE), Departamento de Astrofisica [Madrid], Centro de Astrobiologia [Madrid] (CAB), Instituto Nacional de Técnica Aeroespacial (INTA)-Consejo Superior de Investigaciones Científicas [Spain] (CSIC)-Instituto Nacional de Técnica Aeroespacial (INTA)-Consejo Superior de Investigaciones Científicas [Spain] (CSIC), Spanish Virtual Observatory - Observatorio Virtual Español (SVO), Spanish Virtual Observatory - Observatorio Virtual Español, Department of Computer Science, Università degli Studi di Verona, Space Sciences, Technologies and Astrophysics Research Institute (STAR), Université de Liège, University of Toronto, Laboratory of Information, Network and Communication Sciences (LINCS), Institut Mines-Télécom [Paris] (IMT)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université Pierre et Marie Curie - Paris 6 (UPMC), Dipartimento di Fisica, Politecnico di Milano [Milan] (POLIMI), LEI, Wageningen University and Research [Wageningen] (WUR), Karl-Franzens-Universität Graz, Herpetological Section, Zoologisches Forschungsmuseum Alexander Koenig, Chair of Hydrology, University of Freiburg, Department of Astrophysics [Nijmegen], Institute for Mathematics, Astrophysics and Particle Physics (IMAPP), Radboud university [Nijmegen]-Radboud university [Nijmegen], Department of Computer Science [Beer-Sheva], Ben-Gurion University of the Negev (BGU), The MITRE corporation, Laboratory for Systems, Instrumentation and Modeling in Science and Technology for Space and the Environment (University of Lisbon and University of Beira Interior), Technische Universität Dresden (TUD), Laboratori de Bromatologia i Toxicologia, Facultat de Farmàcia, Universitat de València (UV), Max-Planck-Institut für Sonnensystemforschung (MPS), Max-Planck-Gesellschaft, Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Computer science department [University College London] (UCL-CS), Centre universitaire de Cytométrie, Imagerie et Mathématiques (CIM), Université de Limoges (UNILIM)-CHU Limoges, Department of Gastroenterology and Hepatology, VU University Medical Center [Amsterdam], Institut National de l'Information Géographique et Forestière [IGN] (IGN), ISDC (ISDC), Laboratoire d'Etudes Sociolinguistiques sur les Contacts de Langues et la Politique Linguistique (LESCLAP), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Physics and Astronomy [Clemson], Clemson University, Faculty of Mathematics and Physics [Ljubljana] (FMF), University of Ljubljana, Instituto de Genetica Humana, Pontificia Universidad Javeriana, Universitad de la Sabana, Korea Advanced Institute of Science and Technology (KAIST), Faculty of Pharmacy, Faculty of Information and Communication Technologies, Swinburne University of Technology [Melbourne], Department of Psychiatry, Seaver Autism Center for Research and Treatment, European Southern Observatory (ESO), Centre de Recherches Pétrographiques et Géochimiques (CRPG), Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Service d'Endocrinologie, Diabétologie et Maladies Métaboliques (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Innovalia Association, Department of Physics [Helsinki], Falculty of Science [Helsinki], University of Helsinki-University of Helsinki, Nordic Optical Telescope (NOT), Instituto de Astrofisica de Canarias (IAC), Royal Institute of Technology [Stockholm] (KTH ), Instituto de Astrofísica de Andalucía (IAA), Consejo Superior de Investigaciones Científicas [Spain] (CSIC), EconomiX, Université Paris Nanterre (UPN)-Centre National de la Recherche Scientifique (CNRS), Instituto Nacional de Engenharia, Tecnologia e Inovacco (INETI), Institut d'Astrophysique de Paris (IAP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Réhabilitation Chirurgicale mini-Invasive et Robotisée de l'Audition, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'Otologie, Implants auditifs et Chirurgie de la base du crâne [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), UNINOVA, Faculdade de Ciências e Tecnologia (FCT NOVA), Universidade Nova de Lisboa = NOVA University of Lisboa (NOVA)-Universidade Nova de Lisboa = NOVA University of Lisboa (NOVA), Sonoita Research Observatory, Biologie du fruit et pathologie (BFP), Université Sciences et Technologies - Bordeaux 1-Institut National de la Recherche Agronomique (INRA)-Université Bordeaux Segalen - Bordeaux 2, Institute of Physical Geodesy, Dipartimento di Astronomia [Padova], Universita degli Studi di Padova, Observatoire astronomique de Strasbourg (OAS), Institut national des sciences de l'Univers (INSU - CNRS)-Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Centre d'études spatiales de la biosphère (CESBIO), Centre National d'Études Spatiales [Toulouse] (CNES)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Centre National d'Études Spatiales [Toulouse] (CNES)-Météo France-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo France-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Centre National de la Recherche Scientifique (CNRS), Lohrmann Observatory, Observatoire de la Côte d'Azur (OCA), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de la Côte d'Azur, Université Côte d'Azur (UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Observatoire de Paris, Université Paris sciences et lettres (PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Lille-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR), Institut national des sciences de l'Univers (INSU - CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Université Côte d'Azur (UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Bordeaux (UB), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Côte d'Azur (UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Université Côte d'Azur (UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Université de Lyon-Université de Lyon-École supérieure de Chimie Physique Electronique de Lyon (CPE)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut Mines-Télécom [Paris] (IMT), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Università di Bologna [Bologna] ( UNIBO ), Institut de Physique et Chimie des Matériaux de Strasbourg ( IPCMS ), Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -Matériaux et nanosciences d'Alsace, Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Réseau nanophotonique et optique, Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ), School of Ocean and Earth Science, University of Southampton [Southampton], Istituto Nazionale di Astrofisica ( Istituto Nazionale di Astrofisica ), National Institute for Nuclear Physics ( INFN ), Konkoly Observatory, Research Centre for Astronomy and Earth Sciences, Hungarian Academy of Sciences [Budapest], University of California [Santa Cruz] ( UCSC ), Amsterdam Medical Center, Université de Manchester, Agence Spatiale Européenne ( ESA ), European Space Agency ( ESA ), Equipe EES, Ecologie et biologie des interactions ( EBI ), Université de Poitiers-Centre National de la Recherche Scientifique ( CNRS ) -Université de Poitiers-Centre National de la Recherche Scientifique ( CNRS ), Instituut voor Sterrenkunde, Faculteit Wetenschappen, Galaxies, Etoiles, Physique, Instrumentation ( GEPI ), Institut national des sciences de l'Univers ( INSU - CNRS ) -Observatoire de Paris-Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), University of Illinois at Urbana Champaign ( UIUC ), The Open University [Milton Keynes] ( OU ), Centre National d'Etudes Spatiales ( CNES ), Università degli Studi di Modena e Reggio Emilia [Reggio Emilia] ( UNIMORE ), University of Las Palmas de Gran Canaria ( ULPGC ), Université de Montpellier ( UM ), Universitat de Barcelona ( UB ), Astrophysique Interactions Multi-échelles ( AIM - UMR 7158 - UMR E 9005 ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Diderot - Paris 7 ( UPD7 ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Joseph Louis LAGRANGE ( LAGRANGE ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Observatoire de la Côte d'Azur, Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], European Space Astronomy Center ( ESAC ), Professions, institutions, temporalités ( PRINTEMPS ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Planétologie et Géodynamique de Nantes ( LPG ), Centre National de la Recherche Scientifique ( CNRS ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Université de Nantes ( UN ), Systèmes de Référence Temps Espace ( SYRTE ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Observatoire de Paris-Centre National de la Recherche Scientifique ( CNRS ), FOM Instituut voor Subatomaire Fysica Nikhef, Mullard Space Science Laboratory ( MSSL ), University College of London [London] ( UCL ), Laboratoire d'Electronique et des Technologies de l'Information ( CEA-LETI ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Grenoble Alpes [Saint Martin d'Hères], Royal Observatory of Belgium [Brussels], European Space Astronomy Centre, Institut d'astrophysique spatiale ( IAS ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'Astrophysique de Bordeaux [Pessac] ( LAB ), Université de Bordeaux ( UB ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Bordeaux ( UB ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Picardie Jules Verne ( UPJV ), Laboratoire Univers et Particules de Montpellier ( LUPM ), Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), INAF - Osservatorio Astrofisico di Catania ( OACT ), Istituto Nazionale di Astrofisica ( INAF ), Finnish Geospatial Research Institute ( FGI ), Helsinki Institute of Physics ( HIP ), University of Helsinki [Helsinki], GRAMAT ( DAM/GRAMAT ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Univers, Transport, Interfaces, Nanostructures, Atmosphère et environnement, Molécules (UMR 6213) ( UTINAM ), Université de Franche-Comté ( UFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut national des sciences de l'Univers ( INSU - CNRS ), NASA Goddard Space Flight Center ( GSFC ), Institut de Mécanique Céleste et de Calcul des Ephémérides ( IMCCE ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Observatoire de Paris-Université de Lille-Centre National de la Recherche Scientifique ( CNRS ), Observatoire de Paris - Site de Paris ( OP ), Institut national des sciences de l'Univers ( INSU - CNRS ) -Observatoire de Paris-Centre National de la Recherche Scientifique ( CNRS ), École Centrale de Nantes ( ECN ), University of Cambridge [UK] ( CAM ), Univ. A. I. Cuza, Institut d'écologie et des sciences de l'environnement de Paris ( IEES ), Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Recherche Agronomique ( INRA ), Mount Sinai School of Medicine, Spanish National Research Council ( CSIC ), Università degli studi di Catania [Catania], Institut de Planétologie et d'Astrophysique de Grenoble ( IPAG ), Observatoire des Sciences de l'Univers de Grenoble ( OSUG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Centre National de la Recherche Scientifique ( CNRS ), Université Côte d'Azur ( UCA ), University of New South Wales [Sydney] ( UNSW ), Centre de Recherches Anglophones ( CREA (EA 370) ), Université Paris Nanterre ( UPN ), Centre d'étude spatiale des rayonnements ( CESR ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers ( INSU - CNRS ) -Observatoire Midi-Pyrénées ( OMP ) -Centre National de la Recherche Scientifique ( CNRS ), Observatoire de Haute-Provence ( OHP ), Institut Pythéas ( OSU PYTHEAS ), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture ( IRSTEA ) -Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture ( IRSTEA ) -Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Katholieke Universiteit Leuven ( KU Leuven ), UNS-CNRS-Observatoire de la Côte d'Azur, Centre d'Immunologie et de Maladies Infectieuses ( CIMI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Universidad de las Américas [Puebla] ( UDLAP ), Cognition, Langues, Langage, Ergonomie ( CLLE-ERSS ), École pratique des hautes études ( EPHE ) -Université Toulouse - Jean Jaurès ( UT2J ) -Université Bordeaux Montaigne-Centre National de la Recherche Scientifique ( CNRS ), Scuola Internazionale Superiore di Studi Avanzati / International School for Advanced Studies ( SISSA / ISAS ), Computational Intelligence Research Group [Caparica] ( CA3 ), Universidade Nova de Lisboa ( UNINOVA ) -Centre of Technology and Systems ( CTS ), INAF - Osservatorio Astronomico di Bologna ( OABO ), Géoazur ( GEOAZUR ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Observatoire de la Côte d'Azur, Laboratoire pour l'utilisation des lasers intenses ( LULI ), Université Paris-Saclay-Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -École polytechnique ( X ) -Centre National de la Recherche Scientifique ( CNRS ), INAF - Osservatorio Astrofisico di Torino ( OATo ), Istituto Nazionale di Astrofisica ( INAF ) -Istituto Nazionale di Astrofisica ( INAF ), Universidade de Lisboa ( ULISBOA ), University of León, Observatoire astronomique de Strasbourg ( ObAS ), Université de Strasbourg ( UNISTRA ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), Sciences Pour l'Oenologie ( SPO ), Université Montpellier 1 ( UM1 ) -Institut de Recherche pour le Développement ( IRD [Nouvelle-Calédonie] ) -Institut National de la Recherche Agronomique ( INRA ) -Université de Montpellier ( UM ) -Institut national d’études supérieures agronomiques de Montpellier ( Montpellier SupAgro ), Sciences Po Paris - Institut d'études politiques de Paris ( IEP Paris ), Laboratory of the Institute for Fiscal Studies ( IFS ), Department of Physics (Athens), University of Reading ( UOR ), SRON Netherlands Institute for Space Research ( SRON ), Université Libre de Bruxelles [Bruxelles] ( ULB ), The Institute of Environmental Medicine [Stockholm] ( IMM ), Karolinska Institutet [Stockholm], Virulence bactérienne et maladies infectieuses, Université de Montpellier ( UM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Thérapeutiques Cliniques et Expérimentales des Infections, Université de Nantes ( UN ), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Laboratoire national de métrologie et d'essais - Systèmes de Référence Temps-Espace ( LNE - SYRTE ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Observatoire de Paris-Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Observatoire de Paris-Centre National de la Recherche Scientifique ( CNRS ), Institut de Physique de Rennes ( IPR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ), Chinese Academy of Sciences [Beijing] ( CAS ), Atmel Corporation ( ATMEL ), Institut Camille Jordan [Villeurbanne] ( ICJ ), École Centrale de Lyon ( ECL ), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -Centre National de la Recherche Scientifique ( CNRS ), Astrophysics Research Institute [Liverpool] ( ARI ), Liverpool John Moores University ( LJMU ), Institut de Génomique Fonctionnelle de Lyon ( IGFL ), École normale supérieure - Lyon ( ENS Lyon ) -Institut National de la Recherche Agronomique ( INRA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Matériaux, ingénierie et science [Villeurbanne] ( MATEIS ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ), Institut de Recherche sur la Fusion par confinement Magnétique ( IRFM ), INAF - Osservatorio Astronomico di Trieste ( OAT ), Laboratoire SUBATECH Nantes ( SUBATECH ), Mines Nantes ( Mines Nantes ) -Université de Nantes ( UN ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de l'Accélérateur Linéaire ( LAL ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Centre National de la Recherche Scientifique ( CNRS ), Universidad de Granada ( UGR ), Laboratoire de Physico -& Toxico Chimie des systèmes naturels ( LPTC ), Université Sciences et Technologies - Bordeaux 1-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Cosmologie, Astrophysique Stellaire & Solaire, de Planétologie et de Mécanique des Fluides ( CASSIOPEE ), Centre Atlantique de Philosophie ( CAPHI ), PRES Université Nantes Angers Le Mans ( UNAM ), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique ( CNRS ), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Chimie, Catalyse, Polymères et Procédés, R 5265 ( C2P2 ), Centre National de la Recherche Scientifique ( CNRS ) -École supérieure de Chimie Physique Electronique de Lyon ( CPE ) -Université Claude Bernard Lyon 1 ( UCBL ), Institut de recherche de l'European Business School ( IREBS ), European Business School, Département Réseaux, Information, Multimédia ( RIM-ENSMSE ), École des Mines de Saint-Étienne ( Mines Saint-Étienne MSE ), Institut Mines-Télécom [Paris]-Institut Mines-Télécom [Paris]-Centre G2I, Technische Universität Dortmund [Dortmund] ( TU ), Équipes de Recherches Interlangues : Mémoires, Identités, Territoires ( ERIMIT ), Université de Rennes 2 ( UR2 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ), Université Panthéon-Sorbonne - UFR d'Économie ( UP1 UFR02 ), Université Panthéon-Sorbonne ( UP1 ), Observatoire Astronomique de l'Université de Genève ( ObsGE ), Université de Genève ( UNIGE ), Centro de Astrobiologia, Departamento de Astrofisica ( INTA-CSIC ), Centro de Astrobiología, Spanish Virtual Observatory - Observatorio Virtual Español ( SVO ), Space Sciences, Technologies and Astrophysics Research Institute ( STAR ), Laboratory of Information, Network and Communication Sciences ( LINCS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut Mines-Télécom [Paris], Politecnico di Milano [Milan], Wageningen University and Research Centre [Wageningen] ( WUR ), Institute for Mathematics, Astrophysics and Particle Physics ( IMAPP ), Ben-Gurion University of the Negev ( BGU ), Ben Gurion University, Laboratory for Systems, Instrumentation and Modeling in Science and Technology for Space and the Environment ( University of Lisbon and University of Beira Interior ), Technische Universität Dresden ( TUD ), Mobilités : Vieillissement, Pathologie, Santé ( COMETE ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Universitat de València ( UV ), Max-Planck-Institut für Sonnensystemforschung ( MPS ), Computer science department [University College London] ( UCL-CS ), Centre universitaire de Cytométrie, Imagerie et Mathématiques ( CIM ), Université de Limoges ( UNILIM ) -CHU Limoges, School of psychology, University of Plymouth, Institut National de l'Information Géographique et Forestière [IGN] ( IGN ), ISDC ( ISDC ), Laboratoire d'Etudes Sociolinguistiques sur les Contacts de Langues et la Politique Linguistique ( LESCLAP ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Faculty of Mathematics and Physics [Ljubljana] ( FMF ), Universidad de la Sabana, Korea Advanced Institute of Science and Technology ( KAIST ), Icahn School of Medicine at Mount Sinai [New York], European Southern Observatory ( ESO ), Centre de Recherches Pétrographiques et Géochimiques ( CRPG ), Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Nordic Optical Telescope ( NOT ), Instituto de Astrofisica de Canarias ( IAC ), Royal Institute of Technology [Stockholm] ( KTH ), Instituto de Astrofísica de Andalucía ( IAA ), Consejo Superior de Investigaciones Científicas [Spain] ( CSIC ), Université Paris Nanterre ( UPN ) -Centre National de la Recherche Scientifique ( CNRS ), Instituto Nacional de Engenharia, Tecnologia e Inovacco ( INETI ), INETI, Institut d'Astrophysique de Paris ( IAP ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Institut des sciences analytiques et de physico-chimie pour l'environnement et les materiaux ( IPREM ), Université de Pau et des Pays de l'Adour ( UPPA ) -Centre National de la Recherche Scientifique ( CNRS ), Biologie du fruit et pathologie ( BFP ), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique ( INRA ) -Université Sciences et Technologies - Bordeaux 1, Dipartimento di Astronomia, Observatoire astronomique de Strasbourg ( OAS ), Institut national des sciences de l'Univers ( INSU - CNRS ) -Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique ( CNRS ), Centre d'études spatiales de la biosphère ( CESBIO ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers ( INSU - CNRS ) -Observatoire Midi-Pyrénées ( OMP ) -Centre National d'Etudes Spatiales ( CNES ) -Centre National de la Recherche Scientifique ( CNRS ), Astronomy, Departamento de Inteligencia Artificial, Universidad, National Institute for Nuclear Physics (INFN), PSL Research University (PSL)-PSL Research University (PSL)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Observatoire de la Côte d'Azur, Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Planétologie et Géodynamique UMR6112 (LPG), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Nantes - Faculté des Sciences et des Techniques, Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA), Laboratoire d'Electronique et des Technologies de l'Information (CEA-LETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), PSL Research University (PSL)-PSL Research University (PSL)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut UTINAM (Univers, transport, interfaces, nanostructures, atmosphère et environnement, molécules) (Besançon), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Recherche Agronomique (INRA), Spanish National Research Council (CSIC), Centre National d'Études Spatiales [Toulouse] (CNES)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire des Sciences de l'Univers de Grenoble (OSUG), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, École pratique des hautes études (EPHE)-Université Toulouse - Jean Jaurès (UT2J)-Université Bordeaux Montaigne-Centre National de la Recherche Scientifique (CNRS), Universidade Nova de Lisboa (NOVA)-Universidade Nova de Lisboa (NOVA)-Faculty of Sciences and Technology (FCT NOVA), Universidade Nova de Lisboa (NOVA)-Universidade Nova de Lisboa (NOVA)-Faculdade de Ciências e Tecnologia (FCT NOVA), Universidade Nova de Lisboa (NOVA), Institut national des sciences de l'Univers (INSU - CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Centre National de la Recherche Scientifique (CNRS)-Observatoire de la Côte d'Azur, Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Université Paris-Saclay-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Institut de Recherche pour le Développement (IRD [Nouvelle-Calédonie])-Institut National de la Recherche Agronomique (INRA)-Université de Montpellier (UM)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Université Libre de Bruxelles [Bruxelles] (ULB), PSL Research University (PSL)-PSL Research University (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Wageningen University and Research Centre [Wageningen] (WUR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Institut des sciences analytiques et de physico-chimie pour l'environnement et les materiaux (IPREM), Université de Pau et des Pays de l'Adour (UPPA)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), ITA, GBR, FRA, DEU, ESP, BEL, FIN, Gaia Collaboration, G. Clementini, L. Eyer, V. Ripepi, M. Marconi, T. Muraveva, A. Garofalo, L. M. Sarro, M. Palmer, X. Luri, R. Molinaro, L. Rimoldini, L. Szabado, I. Musella, R. I. Anderson, T. Prusti, J. H. J. de Bruijne, A. G. A. Brown, A. Vallenari, C. Babusiaux, C. A. L. Bailer-Jone, U. Bastian, M. Biermann, D. W. Evan, F. Jansen, C. Jordi, S. A. Klioner, U. Lammer, L. Lindegren, F. Mignard, C. Panem, D. Pourbaix, S. Randich, P. Sartoretti, H. I. Siddiqui, C. Soubiran, V. Valette, F. van Leeuwen, N. A. Walton, C. Aert, F. Arenou, M. Cropper, R. Drimmel, E. Høg, D. Katz, M. G. Lattanzi, W. O'Mullane, E. K. Grebel, A. D. Holland, C. Huc, X. Passot, M. Perryman, L. Bramante, C. Cacciari, J. Castañeda, L. Chaoul, N. Cheek, F. De Angeli, C. Fabriciu, R. Guerra, J. Hernández, A. Jean-Azntoine-Piccolo, E. Masana, R. Messineo, N. Mowlavi, K. Nienartowicz, D. Ordóñez-Blanco, P. Panuzzo, J. Portell, P. J. Richard, M. Riello, G. M. Seabroke, P. Tanga, F. Thévenin, J. Torra, S. G. El, G. Gracia-Abril, G. Comoretto, M. Garcia-Reinaldo, T. Lock, E. Mercier, M. Altmann, R. Andrae, T. L. Astraatmadja, I. Bellas-Velidi, K. Benson, J. Berthier, R. Blomme, G. Busso, B. Carry, A. Cellino, S. Cowell, O. Creevey, J. Cuyper, M. Davidson, J. De Ridder, A. de Torre, L. Delchambre, A. Dell'Oro, C. Ducourant, Y. Frémat, M. García-Torre, E. Gosset, J. -L. Halbwach, N. C. Hambly, D. L. Harrison, M. Hauser, D. Hestroffer, S. T. Hodgkin, H. E. Huckle, A. Hutton, G. Jasniewicz, S. Jordan, M. Kontiza, A. J. Korn, A. C. Lanzafame, M. Manteiga, A. Moitinho, K. Muinonen, J. Osinde, E. Pancino, T. Pauwel, J. -M. Petit, A. Recio-Blanco, A. C. Robin, C. Siopi, M. Smith, K. W. Smith, A. Sozzetti, W. Thuillot, W. van Reeven, Y. Viala, U. Abba, A. Abreu Aramburu, S. Accart, J. J. Aguado, P. M. Allan, W. Allasia, G. Altavilla, M. A. Álvarez, J. Alve, A. H. Andrei, E. Anglada Varela, E. Antiche, T. Antoja, S. Antón, B. Arcay, N. Bach, S. G. Baker, L. Balaguer-Núñez, C. Barache, C. Barata, A. Barbier, F. Barblan, D. Barrado y Navascué, M. Barro, M. A. Barstow, U. Becciani, M. Bellazzini, A. Bello García, V. Belokurov, P. Bendjoya, A. Berihuete, L. Bianchi, O. Bienaymé, F. Billebaud, N. Blagorodnova, S. Blanco-Cuaresma, T. Boch, A. Bombrun, R. Borrachero, S. Bouquillon, G. Bourda, H. Bouy, A. Bragaglia, M. A. Breddel, N. Brouillet, T. Brüsemeister, B. Bucciarelli, P. Burge, R. Burgon, A. Burlacu, D. Busonero, R. Buzzi, E. Caffau, J. Cambra, H. Campbell, R. Cancelliere, T. Cantat-Gaudin, T. Carlucci, J. M. Carrasco, M. Castellani, P. Charlot, J. Charna, A. Chiavassa, M. Clotet, G. Cocozza, R. S. Collin, G. Costigan, F. Crifo, N. J. G. Cro, M. Crosta, C. Crowley, C. Dafonte, Y. Damerdji, A. Dapergola, P. David, M. David, P. De Cat, F. de Felice, P. de Laverny, F. De Luise, R. De March, R. de Souza, J. Debosscher, E. del Pozo, M. Delbo, A. Delgado, H. E. Delgado, P. Di Matteo, S. Diakite, E. Distefano, C. Dolding, S. Dos Anjo, P. Drazino, J. Durán, Y. Dzigan, B. Edvardsson, H. Enke, N. W. Evan, G. Eynard Bontemp, C. Fabre, M. Fabrizio, S. Faigler, A. J. Falcão, M. Farràs Casa, L. Federici, G. Fedoret, J. Fernández-Hernánde, P. Fernique, A. Fienga, F. Figuera, F. Filippi, K. Findeisen, A. Fonti, M. Fouesneau, E. Fraile, M. Fraser, J. Fuch, M. Gai, S. Galleti, L. Galluccio, D. Garabato, F. García-Sedano, N. Garralda, P. Gavra, J. Gerssen, R. Geyer, G. Gilmore, S. Girona, G. Giuffrida, M. Gome, A. González-Marco, J. González-Núñez, J. J. González-Vidal, M. Granvik, A. Guerrier, P. Guillout, J. Guiraud, A. Gúrpide, R. Gutiérrez-Sánchez, L. P. Guy, R. Haigron, D. Hatzidimitriou, M. Haywood, U. Heiter, A. Helmi, D. Hobb, W. Hofmann, B. Holl, G. Holland, J. A. S. Hunt, A. Hypki, V. Icardi, M. Irwin, G. Jevardat de Fombelle, P. Jofré, P. G. Jonker, A. Jorissen, F. Julbe, A. Karampela, A. Kochoska, R. Kohley, K. Kolenberg, E. Kontiza, S. E. Koposov, G. Kordopati, P. Koubsky, A. Krone-Martin, M. Kudryashova, I. Kull, R. K. Bachchan, F. Lacoste-Seri, A. F. Lanza, J. -B. Lavigne, C. Le Poncin-Lafitte, Y. Lebreton, T. Lebzelter, S. Leccia, N. Leclerc, I. Lecoeur-Taibi, V. Lemaitre, H. Lenhardt, F. Leroux, S. Liao, E. Licata, H. E. P. Lindstrøm, T. A. Lister, E. Livanou, A. Lobel, W. Löffler, M. López, D. Lorenz, I. MacDonald, T. Magalhães Fernande, S. Managau, R. G. Mann, G. Mantelet, O. Marchal, J. M. Marchant, S. Marinoni, P. M. Marrese, G. Marschalkó, D. J. Marshall, J. M. Martín-Fleita, M. Martino, N. Mary, G. Matijevič, T. Mazeh, P. J. McMillan, S. Messina, D. Michalik, N. R. Millar, B. M. H. Miranda, D. Molina, M. Molinaro, L. Molnár, M. Moniez, P. Montegriffo, R. Mor, A. Mora, R. Morbidelli, T. Morel, S. Morgenthaler, D. Morri, A. F. Mulone, J. Narbonne, G. Neleman, L. Nicastro, L. Noval, C. Ordénovic, J. Ordieres-Meré, P. Osborne, C. Pagani, I. Pagano, F. Pailler, H. Palacin, L. Palaversa, P. Parson, M. Pecoraro, R. Pedrosa, H. Pentikäinen, B. Pichon, A. M. Piersimoni, F. -X. Pineau, E. Plachy, G. Plum, E. Poujoulet, A. Prša, L. Pulone, S. Ragaini, S. Rago, N. Rambaux, M. Ramos-Lerate, P. Ranalli, G. Rauw, A. Read, S. Regibo, C. Reylé, R. A. Ribeiro, A. Riva, G. Rixon, M. Roelen, M. Romero-Gómez, N. Rowell, F. Royer, L. Ruiz-Dern, G. Sadowski, T. Sagristà Sellé, J. Sahlmann, J. Salgado, E. Salguero, M. Sarasso, H. Savietto, M. Schulthei, E. Sciacca, M. Segol, J. C. Segovia, D. Segransan, I-C. Shih, R. Smareglia, R. L. Smart, E. Solano, F. Solitro, R. Sordo, S. Soria Nieto, J. Souchay, A. Spagna, F. Spoto, U. Stampa, I. A. Steele, H. Steidelmüller, C. A. Stephenson, H. Stoev, F. F. Sue, M. Süvege, J. Surdej, E. Szegedi-Elek, D. Tapiador, F. Tari, G. Tauran, M. B. Taylor, R. Teixeira, D. Terrett, B. Tingley, S. C. Trager, C. Turon, A. Ulla, E. Utrilla, G. Valentini, A. van Elteren, E. Van Hemelryck, M. van Leeuwen, M. Varadi, A. Vecchiato, J. Veljanoski, T. Via, D. Vicente, S. Vogt, H. Vo, V. Votruba, S. Voutsina, G. Walmsley, M. Weiler, K. Weingrill, T. Wever, Ł. Wyrzykowski, A. Yolda, M. Žerjal, S. Zucker, C. Zurbach, T. Zwitter, A. Alecu, M. Allen, C. Allende Prieto, A. Amorim, G. Anglada-Escudé, V. Arsenijevic, S. Azaz, P. Balm, M. Beck, H. -H. Bernstein, L. Bigot, A. Bijaoui, C. Blasco, M. Bonfigli, G. Bono, S. Boudreault, A. Bressan, S. Brown, P. -M. Brunet, P. Bunclark, R. Buonanno, A. G. Butkevich, C. Carret, C. Carrion, L. Chemin, F. Chéreau, L. Corcione, E. Darmigny, K. S. de Boer, P. de Teodoro, P. T. de Zeeuw, C. Delle Luche, C. D. Domingue, P. Dubath, F. Fodor, B. Frézoul, A. Frie, D. Fuste, D. Fyfe, E. Gallardo, J. Gallego, D. Gardiol, M. Gebran, A. Gomboc, A. Gómez, E. Grux, A. Gueguen, A. Heyrovsky, J. Hoar, G. Iannicola, Y. Isasi Parache, A. -M. Janotto, E. Joliet, A. Jonckheere, R. Keil, D. -W. Kim, P. Klagyivik, J. Klar, J. Knude, O. Kochukhov, I. Kolka, J. Ko, A. Kutka, V. Lainey, D. LeBouquin, C. Liu, D. Loreggia, V. V. Makarov, M. G. Marseille, C. Martayan, O. Martinez-Rubi, B. Massart, F. Meynadier, S. Mignot, U. Munari, A. -T. Nguyen, T. Nordlander, K. S. O'Flaherty, P. Ocvirk, A. Olias Sanz, P. Ortiz, J. Osorio, D. Oszkiewicz, A. Ouzouni, P. Park, E. Pasquato, C. Peltzer, J. Peralta, F. Péturaud, T. Pieniluoma, E. Pigozzi, J. Poel, G. Prat, T. Prod'homme, F. Raison, J. M. Rebordao, D. Risquez, B. Rocca-Volmerange, S. Rosen, M. I. Ruiz-Fuerte, F. Russo, S. Sembay, I. Serraller Vizcaino, A. Short, A. Siebert, H. Silva, D. Sinachopoulo, E. Slezak, M. Soffel, D. Sosnowska, V. Straižy, M. ter Linden, D. Terrell, S. Theil, C. Tiede, L. Troisi, P. Tsalmantza, D. Tur, M. Vaccari, F. Vachier, P. Valle, W. Van Hamme, L. Veltz, J. Virtanen, J. -M. Wallut, R. Wichmann, M. I. Wilkinson, H. Ziaeepour, S. Zschocke, Université de Franche-Comté (UFC)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Consejo Superior de Investigaciones Científicas [Spain] (CSIC)-Instituto Nacional de Técnica Aeroespacial (INTA)-Consejo Superior de Investigaciones Científicas [Spain] (CSIC)-Instituto Nacional de Técnica Aeroespacial (INTA), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA)-Institut national des sciences de l'Univers (INSU - CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Centre National de la Recherche Scientifique (CNRS)-Observatoire de la Côte d'Azur, COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Université Côte d'Azur (UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA), École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1, Centre National de la Recherche Scientifique (CNRS)-Observatoire de la Côte d'Azur, COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Université Côte d'Azur (UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA), ESA Scientific Support Office, and Université Côte d'Azur (UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Université Côte d'Azur (UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS)
Subjects: 010504 meteorology & atmospheric sciences, Cepheid variable, GLOBULAR-CLUSTER DISTANCES, Astronomy, [ SDU.ASTR.GA ] Sciences of the Universe [physics]/Astrophysics [astro-ph]/Galactic Astrophysics [astro-ph.GA], GRAVITATIONAL LENSING EXPERIMENT, [SDU.ASTR.EP]Sciences of the Universe [physics]/Astrophysics [astro-ph]/Earth and Planetary Astrophysics [astro-ph.EP], Paral·laxi, Astrophysics, RR Lyrae variable, variables: RR Lyrae [Stars], 01 natural sciences, Linear transformations, data analysis [Methods], 010303 astronomy & astrophysics, ComputingMilieux_MISCELLANEOUS, QC, QB, Physics, Clusters of galaxies, [SDU.ASTR]Sciences of the Universe [physics]/Astrophysics [astro-ph], Settore FIS/05, Parallaxes, Cosmic distance ladder, [ SDU.ASTR.IM ] Sciences of the Universe [physics]/Astrophysics [astro-ph]/Instrumentation and Methods for Astrophysic [astro-ph.IM], Astrometry, distances [Stars], [ SDU.ASTR.EP ] Sciences of the Universe [physics]/Astrophysics [astro-ph]/Earth and Planetary Astrophysics [astro-ph.EP], CLASSICAL CEPHEIDS, Astrophysics - Solar and Stellar Astrophysics, variables: Cepheids [Stars], parallaxes, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, astrometry, Mathematical transformations, [SDU.ASTR.GA]Sciences of the Universe [physics]/Astrophysics [astro-ph]/Galactic Astrophysics [astro-ph.GA], Data release, RADIAL-VELOCITY CURVES, Iodine, PERIOD-LUMINOSITY RELATIONS, Cúmuls de galàxies, stars: variables: RR Lyrae, astro-ph.SR, Astrometria, astro-ph.GA, ESTRELAS VARIÁVEIS, FOS: Physical sciences, Methods: data analysis, Stars: distances, Stars: variables: Cepheids, Stars: variables: RR Lyrae, Astronomy and Astrophysics, Space and Planetary Science, Settore FIS/05 - Astronomia e Astrofisica, VARIABLE-STARS, POPULATION-II-CEPHEIDS, 0103 physical sciences, Curve fitting, GALACTIC CEPHEIDS, Parallax, Methods:data analysis, Solar and Stellar Astrophysics (astro-ph.SR), 0105 earth and related environmental sciences, stars: distances, stars: variables: Cepheids, methods: data analysis, Astrophysics - Astrophysics of Galaxies, HUBBLE-SPACE-TELESCOPE, Galaxies, [PHYS.ASTR.SR]Physics [physics]/Astrophysics [astro-ph]/Solar and Stellar Astrophysics [astro-ph.SR], Geometrical optics, Stars, Galàxies, [SDU.ASTR.IM]Sciences of the Universe [physics]/Astrophysics [astro-ph]/Instrumentation and Methods for Astrophysic [astro-ph.IM], Photometry (astronomy), Luminance, [PHYS.ASTR.GA]Physics [physics]/Astrophysics [astro-ph]/Galactic Astrophysics [astro-ph.GA], [SDU]Sciences of the Universe [physics], Astrophysics of Galaxies (astro-ph.GA), LARGE-MAGELLANIC-CLOUD, Navigations- und Regelungssysteme, [PHYS.ASTR]Physics [physics]/Astrophysics [astro-ph], Linear least squares
Abstract: This work has financially been supported by:... the European Commission's Sixth Framework Programme through the European Leadership in Space Astrometry (ELSA) Marie Curie Research Training Network (MRTN-CT-2006-033481), through Marie Curie project PIOF-GA-2009-255267 (SAS-RRL), and through a Marie Curie Transfer-of-Knowledge (ToK) fellowship (MTKD-CT-2004-014188); the European Commission's Seventh Framework Programme through grant FP7-606740 (FP7-SPACE-2013-1) for the Gaia European Network for Improved data User Services (GENIUS) and through grant 264895 for the Gaia Research for European Astronomy Training (GREAT-ITN) network;the Spanish Ministry of Economy MINECO-FEDER through grants AyA2014-55216, AyA2011-24052, E5P2013-48318-C2-R, and E5P2014-55996-C2-R and MDM-2014-0369 of ICCUB (Unidad de Excelencia Maria de Maeztu)..., Clementini, G., Eyer, L., Ripepi, V., Marconi, M., Muraveva, T., Garofalo, A., Sarro, L.M., Palmer, M., Luri, X., Molinaro, R., Rimoldini, L., Szabados, L., Musella, I., Anderson, R.I., Prusti, T., De Bruijne, J.H.J., Brown, A.G.A., Vallenari, A., Babusiaux, C., Bailer-Jones, C.A.L., Bastian, U., Biermann, M., Evans, D.W., Jansen, F., Jordi, C., Klioner, S.A., Lammers, U., Lindegren, L., Mignard, F., Panem, C., Pourbaix, D., Randich, S., Sartoretti, P., Siddiqui, H.I., Soubiran, C., Valette, V., Van Leeuwen, F., Walton, N.A., Aerts, C., Arenou, F., Cropper, M., Drimmel, R., Høg, E., Katz, D., Lattanzi, M.G., O'Mullane, W., Grebel, E.K., Holland, A.D., Huc, C., Passot, X., Perryman, M., Bramante, L., Cacciari, C., Castañeda, J., Chaoul, L., Cheek, N., De Angeli, F., Fabricius, C., Guerra, R., Hernández, J., Jean-Antoine-Piccolo, A., Masana, E., Messineo, R., Mowlavi, N., Nienartowicz, K., Ordóñez-Blanco, D., Panuzzo, P., Portell, J., Richards, P.J., Riello, M., Seabroke, G.M., Tanga, P., Thévenin, F., Torra, J., Els, S.G., Gracia-Abril, G., Comoretto, G., Garcia-Reinaldos, M., Lock, T., Mercier, E., Altmann, M., Andrae, R., 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Krone-Martins, A., Kudryashova, M., Bachchan, R.K., Lacoste-Seris, F., Lanza, A.F., Lavigne, J.-B., Le Poncin-Lafitte, C., Lebreton, Y., Lebzelter, T., Leccia, S., Leclerc, N., Lecoeur-Taibi, I., Lemaitre, V., Lenhardt, H., Leroux, F., Liao, S., Licata, E., Lindstrøm, H.E.P., Lister, T.A., Livanou, E., Lobel, A., Löffler, W., López, M., Lorenz, D., Macdonald, I., Magalhães Fernandes, T., Managau, S., Mann, R.G., Mantelet, G., Marchal, O., Marchant, J.M., Marinoni, S., Marrese, P.M., Marschalkó, G., Marshall, D.J., Martín-Fleitas, J.M., Martino, M., Mary, N., Matijevič, G., McMillan, P.J., Messina, S., Michalik, D., Millar, N.R., Miranda, B.M.H., Molina, D., Molinaro, M., Molnár, L., Moniez, M., Montegriffo, P., Mor, R., Mora, A., Morbidelli, R., Morel, T., Morgenthaler, S., Morris, D., Mulone, A.F., Narbonne, J., Nelemans, G., Nicastro, L., Noval, L., Ordénovic, C., Ordieres-Meré, J., Osborne, P., Pagani, C., Pagano, I., Pailler, F., Palacin, H., Palaversa, L., Parsons, P., Pecoraro, M., Pedrosa, R., Pentikäinen, H., Pichon, B., Piersimoni, A.M., Pineau, F.-X., Plachy, E., Plum, G., Poujoulet, E., Prša, A., Pulone, L., Ragaini, S., Rago, S., Rambaux, N., Ramos-Lerate, M., Ranalli, P., Rauw, G., Read, A., Regibo, S., Reylé, C., Ribeiro, R.A., Riva, A., Rixon, G., Roelens, M., Romero-Gómez, M., Rowell, N., Royer, F., Ruiz-Dern, L., Sadowski, G., Sagristà Sellés, T., Sahlmann, J., Salgado, J., Salguero, E., Sarasso, M., Savietto, H., Schultheis, M., Sciacca, E., Segol, M., Segovia, J.C., Segransan, D., Shih, I.-C., Smareglia, R., Smart, R.L., Solano, E., Solitro, F., Sordo, R., Soria Nieto, S., Souchay, J., Spagna, A., Spoto, F., Stampa, U., Steele, I.A., Steidelmüller, H., Stephenson, C.A., Stoev, H., Suess, F.F., Süveges, M., Surdej, J., Szegedi-Elek, E., Tapiador, D., Taris, F., Tauran, G., Taylor, M.B., Teixeira, R., Terrett, D., Tingley, B., Trager, S.C., Turon, C., Ulla, A., Utrilla, E., Valentini, G., Van Elteren, A., Van Hemelryck, E., Van Leeuwen, M., Varadi, 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Published: 2017

14. Atad2 is a generalist facilitator of chromatin dynamics in embryonic stem cells

Author: Morozumi, Yuichi, Boussouar, Fayçal, Tan, Minjia, Chaikuad, Apirat, Jamshidikia, Mahya, Colak, Gozde, He, Huang, Nie, Litong, Petosa, Carlo, De Dieuleveult, Maud, Curtet, Sandrine, Vitte, Anne-Laure, Rabatel, Clothilde, Debernardi, Alexandra, François-Loïc, Cosset, Verhoeyen, Els, Emadali, Anouk, Schweifer, Norbert, Gianni, Davide, Gut, Marta, Guardiola, Philippe, Rousseaux, Sophie, Gérard, Matthieu, Knapp, Stefan, Zhao, Yingming, Khochbin, Saadi, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), The Chemical Proteomics Center and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Structural Genomics Consortium, University of Oxford, Nuffield Department of Clinical Medicine [Oxford], Ben May Department of Cancer Research, The University of Chicago Medicine, Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe 'Contrôle Métabolique des Morts Cellulaires' (INSERM U1065 - C3M), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Boehringer Ingelheim RCV, Centre for Genomic Regulation [Barcelona] (CRG), Universitat Pompeu Fabra [Barcelona] (UPF)-Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), University of Oxford [Oxford], Target Discovery Institute (TDI), Nuffield Department of Clinical Medicine, Institut de biologie structurale ( IBS - UMR 5075 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Centre International de Recherche en Infectiologie ( CIRI ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-École normale supérieure - Lyon ( ENS Lyon ), Centre for Genomic Regulation [Barcelona] ( CRG ), Universitat Pompeu Fabra [Barcelona]-Centro Nacional de Analisis Genomico [Barcelona] ( CNAG ), Inserm u892, Centre de Recherches en Cancérologie, Nantes, Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adenosine Triphosphatases, Male, Proteomics, histone turnover, Chromatin Immunoprecipitation, germ cells, Genome, Pax3, [ SDV ] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], FACT, epidrug, Acetylation, Cell Differentiation, Article, Chromatin, Nucleosomes, DNA-Binding Proteins, histone chaperone, ATPases Associated with Diverse Cellular Activities, Humans, cancer drug target, Embryonic Stem Cells, Cell Proliferation, Protein Binding
Abstract: International audience; Although the conserved AAA ATPase and bromodomain factor, ATAD2, has been described as a transcriptional co-activator upregulated in many cancers, its function remains poorly understood. Here, using a combination of ChIP-seq, ChIP-proteomics, and RNA-seq experiments in embryonic stem cells where Atad2 is normally highly expressed, we found that Atad2 is an abundant nucleosome-bound protein present on active genes, associated with chromatin remodelling, DNA replication, and DNA repair factors. A structural analysis of its bromodomain and subsequent investigations demonstrate that histone acetylation guides ATAD2 to chromatin, resulting in an overall increase of chromatin accessibility and histone dynamics, which is required for the proper activity of the highly expressed gene fraction of the genome. While in exponentially growing cells Atad2 appears dispensable for cell growth, in differentiating ES cells Atad2 becomes critical in sustaining specific gene expression programmes, controlling proliferation and differentiation. Altogether, this work defines Atad2 as a facilitator of general chromatin-templated activities such as transcription.
Published: 2016

15. Discovery of pyrido[3,4-g]quinazoline derivatives as CMGC family protein kinase inhibitors: Design, synthesis, inhibitory potency and X-ray co–crystal structure

Author: Francis Giraud, Pascale Moreau, Vincent Théry, Thibaut Boibessot, Yannick J. Esvan, Stefan Knapp, Nadège Loaëc, Fabrice Anizon, Laurent Meijer, Wael Zeinyeh, Apirat Chaikuad, Lionel Nauton, Institut de Chimie de Clermont-Ferrand (ICCF), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-SIGMA Clermont (SIGMA Clermont)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Structural Genomics Consortium, University of Oxford, and ManRos Therapeutics
Subjects: Models, Molecular, 0301 basic medicine, DYRK1A, Protein Conformation, Stereochemistry, 4-g]quinazoline, Chemistry Techniques, Synthetic, Crystal structure, Protein Serine-Threonine Kinases, Crystallography, X-Ray, Pyrido[3, 01 natural sciences, CLK1, Structure-Activity Relationship, 03 medical and health sciences, Drug Discovery, Humans, Transferase, [CHIM]Chemical Sciences, Amino Acid Sequence, Ser/Thr kinases, Protein kinase A, Protein Kinase Inhibitors, Pharmacology, chemistry.chemical_classification, 010405 organic chemistry, Chemistry, CMGC family, Cyclin-dependent kinase 5, Organic Chemistry, General Medicine, Combinatorial chemistry, 3. Good health, 0104 chemical sciences, CLK1 binding mode, 030104 developmental biology, Kinase inhibitors, Drug Design, Quinazolines, Casein kinase 1, Tricyclic
Abstract: International audience; The design and synthesis of new pyrido[3,4-g]quinazoline derivatives is described as well as their protein kinase inhibitory potencies toward five CMGC family members (CDK5, CK1, GSK3, CLK1 and DYRK1A). The interest for this original tricyclic heteroaromatic scaffold as modulators of CLK1/DYRK1A activity was validated by nanomolar potencies (compounds 12 and 13). CLK1 co–crystal structures with two inhibitors revealed the binding mode of these compounds within the ATP-binding pocket.
Published: 2016

16. Redox Behavior of the S-Adenosylmethionine (SAM)-Binding Fe-S Cluster in Methylthiotransferase RimO, toward Understanding Dual SAM Activity

Author: Jean-Luc Ravanat, Martin Clémancey, Yohann Moreau, Farhad Forouhar, Mohamed G. Atta, Jean-Marc Latour, Etienne Mulliez, Nicolas Duraffourg, Serge Gambarelli, Thibaut Molle, Vincent Fourmond, Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Biological Sciences, Columbia University, New York, New York, USA., Columbia University [New York], Northeast Structural Genomics Consortium, Laboratoire Lésions des Acides Nucléiques (LAN), Service de Chimie Inorganique et Biologique (SCIB - UMR E3), Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS), Bioénergétique et Ingénierie des Protéines (BIP ), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
Subjects: Iron-Sulfur Proteins, 0301 basic medicine, S-Adenosylmethionine, Reaction mechanism, 010402 general chemistry, 01 natural sciences, Biochemistry, Chemical reaction, Redox, Catalysis, Cofactor, law.invention, 03 medical and health sciences, law, Cluster (physics), Molecule, [CHIM]Chemical Sciences, Electron paramagnetic resonance, biology, Chemistry, Escherichia coli Proteins, Spectrum Analysis, 0104 chemical sciences, 3. Good health, Crystallography, 030104 developmental biology, Sulfurtransferases, Mutagenesis, Site-Directed, biology.protein, Density functional theory, Oxidation-Reduction
Abstract: International audience; RimO, a radical-S-adenosylmethionine (SAM) enzyme, catalyzes the specific C3 methylthiolation of the D89 residue in the ribosomal S12 protein. Two intact iron–sulfur clusters and two SAM cofactors both are required for catalysis. By using electron paramagnetic resonance, Mössbauer spectroscopies, and site-directed mutagenesis, we show how two SAM molecules sequentially bind to the unique iron site of the radical-SAM cluster for two distinct chemical reactions in RimO. Our data establish that the two SAM molecules bind the radical-SAM cluster to the unique iron site, and spectroscopic evidence obtained under strongly reducing conditions supports a mechanism in which the first molecule of SAM causes the reoxidation of the reduced radical-SAM cluster, impeding reductive cleavage of SAM to occur and allowing SAM to methylate a HS– ligand bound to the additional cluster. Furthermore, by using density functional theory-based methods, we provide a description of the reaction mechanism that predicts the attack of the carbon radical substrate on the methylthio group attached to the additional [4Fe-4S] cluster.
Published: 2016

17. Codon influence on protein expression in E. coli correlates with mRNA levels

Author: Gaetano T. Montelione, W. Nicholson Price, Mayank Valecha, Reka Letso, Thomas Acton, Kam Ho Wong, Grégory Boël, Helen Neely, Min Su, Daniel P. Aalberts, Jon D. Luff, Rong Xiao, John F. Hunt, John K. Everett, Expression Génétique Microbienne (EGM (UMR_8261 / FRE_3630)), Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Northeast Structural Genomics Consortium, Columbia University [New York], and Institut de biologie physico-chimique (IBPC)
Subjects: 0301 basic medicine, RNA Folding, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Transcription, Genetic, RNA Stability, Molecular Sequence Data, Peptide Chain Elongation, Translational, Biology, Article, 03 medical and health sciences, Viral Proteins, Transcription (biology), Protein biosynthesis, Escherichia coli, Genes, Synthetic, Odds Ratio, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Codon, Gene, ComputingMilieux_MISCELLANEOUS, Regulation of gene expression, Genetics, Messenger RNA, Multidisciplinary, Models, Genetic, Escherichia coli Proteins, RNA, DNA-Directed RNA Polymerases, Gene Expression Regulation, Bacterial, Genetic code, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Kinetics, RNA, Bacterial, 030104 developmental biology, Logistic Models, Codon usage bias, Protein Biosynthesis, Half-Life
Abstract: Degeneracy in the genetic code, which enables a single protein to be encoded by a multitude of synonymous gene sequences, has an important role in regulating protein expression, but substantial uncertainty exists concerning the details of this phenomenon. Here we analyse the sequence features influencing protein expression levels in 6,348 experiments using bacteriophage T7 polymerase to synthesize messenger RNA in Escherichia coli. Logistic regression yields a new codon-influence metric that correlates only weakly with genomic codon-usage frequency, but strongly with global physiological protein concentrations and also mRNA concentrations and lifetimes in vivo. Overall, the codon content influences protein expression more strongly than mRNA-folding parameters, although the latter dominate in the initial ~16 codons. Genes redesigned based on our analyses are transcribed with unaltered efficiency but translated with higher efficiency in vitro. The less efficiently translated native sequences show greatly reduced mRNA levels in vivo. Our results suggest that codon content modulates a kinetic competition between protein elongation and mRNA degradation that is a central feature of the physiology and also possibly the regulation of translation in E. coli.
Published: 2016

18. A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells

Author: Sylvie Rival-Gervier, Bryan L. Roth, Cheryl H. Arrowsmith, Abdellah Allali-Hassani, Alena Siarheyeva, Xi Ping Huang, Dmitri Kireev, William P. Janzen, Jian Jin, Peter Brown, Aled M. Edwards, Arturas Petronis, Tim J. Wigle, Feng Liu, Viviane Labrie, Irene Chau, Peter A. DiMaggio, Thomas J. Mangano, Aiping Dong, Wolfram Tempel, Sun Chong Wang, Xin Chen, Gregory A. Wasney, Benjamin A. Garcia, Jacqueline L. Norris, Masoud Vedadi, Ashutosh Tripathy, Stephen V. Frye, Catherine Simpson, James Ellis, Dalia Barsyte-Lovejoy, Samantha G. Pattenden, Structural Genomics Consortium, University of Toronto, Division of Medicinal Chemistry and Natural Products, Center for Integrative Chemical Biology and Drug Discovery, Biologie du Développement et Reproduction (BDR), Institut National de la Recherche Agronomique (INRA), Krembil Family Epigenetic Laboratory, Centre of Addiction and Mental Health, Department of Chemistry, Princeton University, Division of Medical Chemistry and Natural Products, UNC Eshelman School of Pharmacy, Department of Biochemistry and Biophysics, UNC Macromolecular Interactions Facility, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Development and Stem Cell Biology Program, Hospital for Sick Children, Department of Molecular Genetics, Campbell Family Center Research Institute and Department of medical Biophysics, Ontaria Cancer Institute, Biologie du développement et reproduction (BDR), and Centre National de la Recherche Scientifique (CNRS)-École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)
Subjects: p53, [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Methyltransferase, g9a protéine, dna methylation, Biology, Article, Cell Line, micro rna, EHMT2, Small hairpin RNA, Mice, 03 medical and health sciences, Histone H3, 0302 clinical medicine, stem cells, chip chip, histone lysine n methyltransferase, Animals, Humans, Gene Silencing, Epigenetics, Enzyme Inhibitors, Molecular Biology, mouse, 030304 developmental biology, chromatin structure, complexes, 0303 health sciences, Reporter gene, Gene knockdown, Molecular Structure, glp protéine, unc0638, Histone-Lysine N-Methyltransferase, lysine 9 methylation, Cell Biology, Cell biology, Biochemistry, 030220 oncology & carcinogenesis, DNA methylation, Quinazolines, gene expression, cancer cells, methyltransferase, pluripotent stem cells, transcription, repression, epigenetic
Abstract: Erratum : Nat. Chem. Biol. 2011 7(9):648 2011 7(8): following 574 ; Protein lysine methyltransferases G9a and GLP modulate the transcriptional repression of a variety of genes via dimethylation of Lys9 on histone H3 (H3K9me2) as well as dimethylation of non-histone targets. Here we report the discovery of UNC0638, an inhibitor of G9a and GLP with excellent potency and selectivity over a wide range of epigenetic and non-epigenetic targets. UNC0638 treatment of a variety of cell lines resulted in lower global H3K9me2 levels, equivalent to levels observed for small hairpin RNA knockdown of G9a and GLP with the functional potency of UNC0638 being well separated from its toxicity. UNC0638 markedly reduced the clonogenicity of MCF7 cells, reduced the abundance of H3K9me2 marks at promoters of known G9a-regulated endogenous genes and disproportionately affected several genomic loci encoding microRNAs. In mouse embryonic stem cells, UNC0638 reactivated G9a-silenced genes and a retroviral reporter gene in a concentration-dependent manner without promoting differentiation.
Published: 2011

19. Molecular basis for the methylation specificity of ATXR5 for histone H3

Author: S. Yeung, Masoud Vedadi, Jean-François Couture, Joseph S. Brunzelle, E. Bergamin, J. Malette, Scott D. Michaels, Alexandre Blais, M. Joshi, Mohammad S. Eram, Sabina Sarvan, Mongeon, Structural Genomics Consortium, University of Toronto, and University of Ottawa [Ottawa]
Subjects: 0301 basic medicine, Models, Molecular, Amino Acid Motifs, Arabidopsis, SAP30, Biology, Crystallography, X-Ray, Methylation, Substrate Specificity, Histones, 03 medical and health sciences, Histone H3, Gene Expression Regulation, Plant, Catalytic Domain, Histone H2A, Histone methylation, Genetics, Nucleosome, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Epigenomics, 030102 biochemistry & molecular biology, Arabidopsis Proteins, Gene regulation, Chromatin and Epigenetics, Hydrogen Bonding, Methyltransferases, Molecular biology, Cell biology, Kinetics, 030104 developmental biology, Histone, Histone methyltransferase, biology.protein, Hydrophobic and Hydrophilic Interactions, Protein Processing, Post-Translational, Protein Binding
Abstract: In plants, the histone H3.1 lysine 27 (H3K27) mono-methyltransferases ARABIDOPSIS TRITHORAX RELATED PROTEIN 5 and 6 (ATXR5/6) regulate heterochromatic DNA replication and genome stability. Our initial studies showed that ATXR5/6 discriminate between histone H3 variants and preferentially methylate K27 on H3.1. In this study, we report three regulatory mechanisms contributing to the specificity of ATXR5/6. First, we show that ATXR5 preferentially methylates the R/F-K*-S/C-G/A-P/C motif with striking preference for hydrophobic and aromatic residues in positions flanking this core of five amino acids. Second, we demonstrate that post-transcriptional modifications of residues neighboring K27 that are typically associated with actively transcribed chromatin are detrimental to ATXR5 activity. Third, we show that ATXR5 PHD domain employs a narrow binding pocket to selectively recognize unmethylated K4 of histone H3. Finally, we demonstrate that deletion or mutation of the PHD domain reduces the catalytic efficiency (kcat/Km of AdoMet) of ATXR5 up to 58-fold, highlighting the multifunctional nature of ATXR5 PHD domain. Overall, our results suggest that several molecular determinants regulate ATXR5/6 methyltransferase activity and epigenetic inheritance of H3.1 K27me1 mark in plants.
Published: 2015

20. Two Fe-S clusters catalyze sulfur insertion by radical-SAM methylthiotransferases

Author: Jean Marie Mouesca, Serge Gambarelli, Sylvie Kieffer-Jaquinod, Simon Arragain, John F. Hunt, Rong Xiao, Thomas Acton, Mohamed G. Atta, Farhad Forouhar, Jayaraman Seetharaman, Etienne Mulliez, Marc Fontecave, Munif Hussain, Gaetano T. Montelione, Northeast Structural Genomics Consortium, Columbia University [New York], Department of Biological Sciences, Columbia University, New York, New York, USA., Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service de Chimie Inorganique et Biologique (SCIB - UMR E3), Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS), Center for Advanced Biotechnology and Medicine, Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey, USA., Rutgers, The State University of New Jersey [New Brunswick] (RU), Rutgers University System (Rutgers)-Rutgers University System (Rutgers), Department of Biochemistry, Robert Wood Johnson Medical School, Piscataway, New Jersey, USA., Rutgers Biomedical and Health Sciences, Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Collège de France - Chaire Chimie des processus biologiques, Laboratoire de Chimie des Processus Biologiques (LCPB), Collège de France (CdF (institution))-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Collège de France (CdF (institution))-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Chaire Chimie des processus biologiques
Subjects: inorganic chemicals, Iron-Sulfur Proteins, Models, Molecular, S-Adenosylmethionine, MIAB PROTEIN, Free Radicals, Stereochemistry, TRANSFER-RNA, Sulfur metabolism, Sulfurtransferase, chemistry.chemical_element, Biotin synthase, Crystallography, X-Ray, 010402 general chemistry, 01 natural sciences, Article, Cofactor, 03 medical and health sciences, Polymer chemistry, Molecule, Thermotoga maritima, CRYSTAL-STRUCTURE, DEPENDENT ENZYME MOAA, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, 030304 developmental biology, 0303 health sciences, Molecular Structure, biology, Chemistry, IRON, METHYLATION, Cell Biology, [CHIM.CATA]Chemical Sciences/Catalysis, Sulfur, 0104 chemical sciences, Biocatalysis, ESCHERICHIA-COLI, Sulfurtransferases, RESPONSE REGULATOR NARL, DENSITY, biology.protein, BIOTIN SYNTHASE, Radical SAM
Abstract: International audience; How living organisms create carbon-sulfur bonds during the biosynthesis of critical sulfur-containing compounds is still poorly understood. The methylthiotransferases MiaB and RimO catalyze sulfur insertion into tRNAs and ribosomal protein S12, respectively. Both belong to a subgroup of radical–S-adenosylmethionine (radical-SAM) enzymes that bear two [4Fe-4S] clusters. One cluster binds S-adenosylmethionine and generates an Ado• radical via a well-established mechanism. However, the precise role of the second cluster is unclear. For some sulfur-inserting radical-SAM enzymes, this cluster has been proposed to act as a sacrificial source of sulfur for the reaction. In this paper, we report parallel enzymological, spectroscopic and crystallographic investigations of RimO and MiaB, which provide what is to our knowledge the first evidence that these enzymes are true catalysts and support a new sulfation mechanism involving activation of an exogenous sulfur cosubstrate at an exchangeable coordination site on the second cluster, which remains intact during the reaction.
Published: 2013

21. A new powerful tool to decipher retroviral vector silencing mechanisms in pluripotent cells

Author: Rival, Sylvie, Baryste-Lovejoy, Dalia, Lo, Mandy, Anderson, Susan, Pasceri, Peter, Jin, Jian, Arrowsmith, Cheryl H., Ellis, James, Biologie du développement et reproduction (BDR), Centre National de la Recherche Scientifique (CNRS)-École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), University of Toronto, Structural Genomics Consortium, University of North Carolina, Mc Master University. CAN., and ProdInra, Migration
Subjects: [SDV.BDD] Life Sciences [q-bio]/Development Biology, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, [SDV.BDD]Life Sciences [q-bio]/Development Biology, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2011

22. The D4Z4 insulator protects retrovirus transgenes from silencing in pluripotent stem cells

Author: Rival-Gervier, Sylvie, Barsyte-Lovejoy, Dalia, Lo, Mandy, Anderson, Susan, Pasceri, Peter, Jin, Jian, Arrowsmith, Cheryl H., Ellis, James, Biologie du développement et reproduction (BDR), Centre National de la Recherche Scientifique (CNRS)-École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), University of Toronto, Structural Genomics Consortium, University of North Carolina, Epigenetics. CAN., International Society of Stem Cell Research (ISSCR). INT., and ProdInra, Migration
Subjects: d4z4, [SDV.BDD] Life Sciences [q-bio]/Development Biology, isolant, [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2011

23. Post-translational modification of ribosomal proteins: structural and functional characterization of RimO from Thermotoga maritima, a radical S-adenosylmethionine methylthiotransferase

Author: Arragain, Simon, Garcia-Serres, Ricardo, Blondin, Geneviève, Douki, Thierry, Clemancey, Martin, Latour, Jean-Marc, Forouhar, Farhad, Neely, Helen, Montelione, Gaetano T, Hunt, John F, Mulliez, Etienne, Fontecave, Marc, Atta, Mohamed, Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire Lésions des Acides Nucléiques (LAN), Service de Chimie Inorganique et Biologique (SCIB - UMR E3), Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS), Northeast Structural Genomics Consortium, Columbia University [New York], Department of Biological Sciences [New York], Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey [New Brunswick] (RU), Rutgers University System (Rutgers)-Rutgers University System (Rutgers), Chaire Chimie des processus biologiques, Laboratoire de Chimie des Processus Biologiques (LCPB), Collège de France (CdF (institution))-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Collège de France (CdF (institution))-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Collège de France - Chaire Chimie des processus biologiques
Subjects: Ribosomal Proteins, S-Adenosylmethionine, Structure-Activity Relationship, Sulfurtransferases, Enzymology, Thermotoga maritima, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Crystallography, X-Ray, Protein Processing, Post-Translational, Protein Structure, Tertiary
Abstract: International audience; Post-translational modifications of ribosomal proteins are important for the accuracy of the decoding machinery. A recent in vivo study has shown that the rimO gene is involved in generation of the 3-methylthio derivative of residue Asp-89 in ribosomal protein S12 (Anton, B. P., Saleh, L., Benner, J. S., Raleigh, E. A., Kasif, S., and Roberts, R. J. (2008) Proc. Natl. Acad. Sci. U. S. A. 105, 1826-1831). This reaction is formally identical to that catalyzed by MiaB on the C2 of adenosine 37 near the anticodon of several tRNAs. We present spectroscopic evidence that Thermotoga maritima RimO, like MiaB, contains two [4Fe-4S] centers, one presumably bound to three invariant cysteines in the central radical S-adenosylmethionine (AdoMet) domain and the other to three invariant cysteines in the N-terminal UPF0004 domain. We demonstrate that holo-RimO can specifically methylthiolate the aspartate residue of a 20-mer peptide derived from S12, yielding a mixture of mono- and bismethylthio derivatives. Finally, we present the 2.0 A crystal structure of the central radical AdoMet and the C-terminal TRAM (tRNA methyltransferase 2 and MiaB) domains in apo-RimO. Although the core of the open triose-phosphate isomerase (TIM) barrel of the radical AdoMet domain was conserved, RimO showed differences in domain organization compared with other radical AdoMet enzymes. The unusually acidic TRAM domain, likely to bind the basic S12 protein, is located at the distal edge of the radical AdoMet domain. The basic S12 protein substrate is likely to bind RimO through interactions with both the TRAM domain and the concave surface of the incomplete TIM barrel. These biophysical results provide a foundation for understanding the mechanism of methylthioation by radical AdoMet enzymes in the MiaB/RimO family.
Published: 2010

24. Potent, Selective, and Cell-active Chemical Probe of Protein Lysine Methyltransferases G9a and GLP: Cell-Based Assays

Author: Dalia Baryste-Lovejoy, Sylvie Rival-Gervier, Feng Liu, Abdellah Allali-Hassani, Wigle, Tim J., Dimaggio, Peter A., Gregory, A. Wasney, Alena Siarheyeva, Aiping Dong, Wolfram Tempel, Xin Chen, Irene Chau, Mangano, Thomas J., Evans, Jon M., Simpson, Catherine D., Samantha, G. Pattenden, Norris, Jacqueline L., Kireev, Dmitri B., Ashutosh Tripathy, Aled Edwards, Bryan Roth, Janzen, William P., Garcia, Benjamin A., Brown, Petyer J., Frye, Stephen V., Masoud Vedadi, James Ellis, Jian Jin, Arrowsmith, Cheryl H., ProdInra, Migration, Structural Genomics Consortium, University of Toronto, Biologie du développement et reproduction (BDR), Centre National de la Recherche Scientifique (CNRS)-École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Division of Medicinal Chemistry and Natural Products, Center for Integrative Chemical Biology and Drug Discovery, Department of Chemistry, Princeton University, and University of North Carolina
Subjects: [SDV] Life Sciences [q-bio], CELLULES EMBRYONNAIRES DE SOURIS, RETROVIRAL VECTOR, [SDV]Life Sciences [q-bio], MOUSE EMBRYONIC STEM CELLS, bacteria, [INFO]Computer Science [cs], G9A METHYLTRANSFERASE, [INFO] Computer Science [cs], complex mixtures, VECTEUR RETROVIRAL, METHYLTRANSFERASE G9A, SILENCING
Abstract: International audience; Histone lysine methylation is important epigenetic mark that regulates chromatin structure and gene expression. G9a and GLP lysine methyltransferases dimethylate lysine 9 on histone H3 and repress gene transcription playing roles in development, cancer, pluripotency and other biological processes. We report the development of UNC0638 as a chemical probe of G9a/GLP, active in a cellular system at nM concentrations, with excellent toxicity/potency ratio and low nM in vitro potency and selectivity for G9a/GLP over a wide range of targets. Cell immunofluorescence assay/ Incell Western as fast, reproducible and high throughput cellular assay measuring the levels of dimethylated histone H3 lysine 9 was developed and validated using G9a and GLP knockdowns. High G9a/GLP selectivity for lysine 9 dimethyl modification on histone H3 was also established by the mass spectrometry. In mouse ES cells, UNC0638 reactivated silenced GFP reporter
Published: 2010

25. Molecular Insights into the Biosynthesis of the F420 Coenzyme*

Author: Robert H. White, Jayaraman Seetharaman, Gaetano T. Montelione, Farhad Forouhar, Yang Chen, Thomas Acton, Liang Tong, Anne Galinier, Huimin Xu, Weihong Zhou, Rong Xiao, Alexandre P. Kuzin, Laura L. Grochowski, Mariam Abashidze, Munif Hussain, Northeast Structural Genomics Consortium, Columbia University [New York], BNMRC Peking University, Centre de Recherche en Information Biomédicale sino-français (CRIBS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Southeast University [Jiangsu]-Institut National de la Santé et de la Recherche Médicale (INSERM), Lanzhou University, Ontario Research Center for Computer Algebra (ORCCA), University of Waterloo [Waterloo]-University of Western Ontario (UWO), National University of Ireland [Galway] (NUI Galway), Laboratoire de chimie bactérienne (LCB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Peking University [Beijing], and Université de Rennes (UR)-Southeast University [Jiangsu]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Rossmann fold, DNA Repair, Stereochemistry, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Molecular Conformation, Biochemistry, Cofactor, Catalysis, 03 medical and health sciences, chemistry.chemical_compound, Transferase, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, NADH, NADPH Oxidoreductases, Amino Acid Sequence, Binding site, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Binding Sites, biology, Polyglutamate, Enzyme Catalysis and Regulation, Sequence Homology, Amino Acid, 030306 microbiology, Active site, Cell Biology, Methanosarcina, biology.organism_classification, Coenzyme F420, Protein Structure, Tertiary, chemistry, Gene Expression Regulation, Microscopy, Fluorescence, Models, Chemical, biology.protein, Dimerization, Protein Binding
Abstract: Coenzyme F420, a hydride carrier, is found in Archaea and some bacteria and has crucial roles in methanogenesis, antibiotic biosynthesis, DNA repair, and activation of antitubercular compounds. CofD, 2-phospho-l-lactate transferase, catalyzes the last step in the biosynthesis of F420-0 (F420 without polyglutamate), by transferring the lactyl phosphate moiety of lactyl(2)diphospho-(5′)guanosine to 7,8-didemethyl-8-hydroxy-5-deazariboflavin ribitol (Fo). CofD is highly conserved among F420-producing organisms, and weak sequence homologs are also found in non-F420-producing organisms. This superfamily does not share any recognizable sequence conservation with other proteins. Here we report the first crystal structures of CofD, the free enzyme and two ternary complexes, with Fo and Pi or with Fo and GDP, from Methanosarcina mazei. The active site is located at the C-terminal end of a Rossmann fold core, and three large insertions make significant contributions to the active site and dimer formation. The observed binding modes of Fo and GDP can explain known biochemical properties of CofD and are also supported by our binding assays. The structures provide significant molecular insights into the biosynthesis of the F420 coenzyme. Large structural differences in the active site region of the non-F420-producing CofD homologs suggest that they catalyze a different biochemical reaction.
Published: 2008

26. Identification of a cell-active chikungunya virus nsP2 protease inhibitor using a covalent fragment-based screening approach.

Author: Merten EM, Sears JD, Leisner TM, Hardy PB, Ghoshal A, Hossain MA, Asressu KH, Brown PJ, Tse EG, Stashko MA, Li K, Norris-Drouin JL, Herring LE, Mordant AL, Webb TS, Mills CA, Barker NK, Streblow ZJ, Perveen S, Arrowsmith CH, Couñago RM, Arnold JJ, Cameron CE, Streblow DN, Moorman NJ, Heise MT, Willson TM, Popov KI, and Pearce KH
Subjects: Virus Replication drug effects, Antiviral Agents pharmacology, Antiviral Agents chemistry, Humans, Protease Inhibitors pharmacology, Protease Inhibitors chemistry, Sulfones pharmacology, Sulfones chemistry, Animals, Chikungunya Fever virology, Chikungunya Fever drug therapy, Chikungunya virus drug effects, Cysteine Endopeptidases metabolism, Cysteine Endopeptidases chemistry
Abstract: Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has been responsible for numerous large-scale outbreaks in the last twenty years. Currently, there are no FDA-approved therapeutics for any alphavirus infection. CHIKV nonstructural protein 2 (nsP2), which contains a cysteine protease domain, is essential for viral replication, making it an attractive target for a drug discovery campaign. Here, we optimized a CHIKV nsP2 protease (nsP2pro) biochemical assay for the screening of a 6,120-compound cysteine-directed covalent fragment library. Using a 50% inhibition threshold, we identified 153 hits (2.5% hit rate). In dose-response follow-up, RA-0002034, a covalent fragment that contains a vinyl sulfone warhead, inhibited CHIKV nsP2pro with an IC 50 of 58 ± 17 nM, and further analysis with time-dependent inhibition studies yielded a k inact /K I of 6.4 × 10 3 M -1 s -1 . LC-MS/MS analysis determined that RA-0002034 covalently modified the catalytic cysteine in a site-specific manner. Additionally, RA-0002034 showed no significant off-target reactivity in proteomic experiments or against a panel of cysteine proteases. In addition to the potent biochemical inhibition of CHIKV nsP2pro activity and exceptional selectivity, RA-0002034 was tested in cellular models of alphavirus infection and effectively inhibited viral replication of both CHIKV and related alphaviruses. This study highlights the identification and characterization of the chemical probe RA-0002034 as a promising hit compound from covalent fragment-based screening for development toward a CHIKV or pan-alphavirus therapeutic., Competing Interests: Competing interests statement:The authors declare no competing interest.
Published: 2024
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27. The use of a multi-metric readout screen to identify EHMT2/G9a-inhibition as a modulator of cancer-associated fibroblast activation state.

Author: Wu NC, Quevedo R, Nurse M, Hezaveh K, Liu H, Sun F, Muffat J, Sun Y, Simmons CA, McGaha TL, Prinos P, Arrowsmith CH, Ailles L, D'Arcangelo E, and McGuigan AP
Abstract: Cancer-associated fibroblasts (CAFs) play a pivotal role in cancer progression, including mediating tumour cell invasion via their pro-invasive secretory profile and ability to remodel the extracellular matrix (ECM). Given that reduced CAF abundance in tumours correlates with improved outcomes in various cancers, we set out to identify epigenetic targets involved in CAF activation in regions of tumour-stromal mixing with the goal of reducing tumour aggressiveness. Using the GLAnCE (Gels for Live Analysis of Compartmentalized Environments) platform, we performed an image-based, phenotypic screen that enabled us to identify modulators of CAF abundance and the capacity of CAFs to induce tumour cell invasion. We identified EHMT2 (also known as G9a), an enzyme that targets the methylation of histone 3 lysine 9 (H3K9), as a potent modulator of CAF abundance and CAF-mediated tumour cell invasion. Transcriptomic and functional analysis of EHMT2-inhibited CAFs revealed EHMT2 participated in driving CAFs towards a pro-invasive phenotype and mediated CAF hyperproliferation, a feature typically associated with activated fibroblasts in tumours. Our study suggests that EHMT2 regulates CAF state within the tumour microenvironment by impacting CAF activation, as well as by magnifying the pro-invasive effects of these activated CAFs on tumour cell invasion through promoting CAF hyperproliferation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Published: 2024
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28. Synthesis and evaluation of chemical linchpins for highly selective CK2α targeting.

Author: Greco FA, Krämer A, Wahl L, Elson L, Ehret TAL, Gerninghaus J, Möckel J, Müller S, Hanke T, and Knapp S
Subjects: Humans, Structure-Activity Relationship, Molecular Structure, Dose-Response Relationship, Drug, Models, Molecular, Adenosine Triphosphate metabolism, Binding Sites, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Casein Kinase II antagonists & inhibitors, Casein Kinase II metabolism
Abstract: Casein kinase-2 (CK2) are serine/threonine kinases with dual co-factor (ATP and GTP) specificity, that are involved in the regulation of a wide variety of cellular functions. Small molecules targeting CK2 have been described in the literature targeting different binding pockets of the kinase with a focus on type I inhibitors such as the recently published chemical probe SGC-CK2-1. In this study, we investigated whether known allosteric inhibitors binding to a pocket adjacent to helix αD could be combined with ATP mimetic moieties defining a novel class of ATP competitive compounds with a unique binding mode. Linking both binding sites requires a chemical linking moiety that would introduce a 90-degree angle between the ATP mimetic ring system and the αD targeting moiety, which was realized using a sulfonamide. The synthesized inhibitors were highly selective for CK2 with binding constants in the nM range and low micromolar activity. While these inhibitors need to be further improved, the present work provides a structure-based design strategy for highly selective CK2 inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Published: 2024
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29. An Adenosine Analogue Library Reveals Insights into Active Sites of Protein Arginine Methyltransferases and Enables the Discovery of a Selective PRMT4 Inhibitor.

Author: Deng Y, Kim EJ, Song X, Kulkarni AS, Zhu RX, Wang Y, Bush M, Dong A, Noinaj N, Min J, Xu W, and Huang R
Abstract: Protein arginine methyltransferases (PRMTs) represent promising drug targets. However, the lack of isoform-selective chemical probes poses a significant hurdle in deciphering their biological roles. To address this issue, we devised a library of 100 diverse adenosine analogues, enabling a detailed exploration of the active site of PRMTs. Despite their close homology, our analysis unveiled specific chemical trends unique to the individual members. Notably, compound YD1130 demonstrated over 1000-fold selectivity for PRMT4 (IC 50 < 0.5 nM) over a panel of 38 methyltransferases, including the other PRMTs. Its prodrug YD1342 exhibited potent inhibition on cellular substrate methylation, breast cancer cell colony formation, and tumor growth in the animal model, surpassing or matching known PRMT4-specific inhibitors. In summary, our focused library not only illuminates the intricate active sites of PRMTs to facilitate the discovery of highly potent and isoform-selective probes but also offers a versatile blueprint for identifying chemical probes for other methyltransferases.
Published: 2024
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30. Poly ADP-ribose signaling is dysregulated in Huntington disease.

Author: Maiuri T, Bazan CB, Harding RJ, Begeja N, Kam TI, Byrne LM, Rodrigues FB, Warner MM, Neuman K, Mansoor M, Badiee M, Dasovich M, Wang K, Thompson LM, Leung AKL, Andres SN, Wild EJ, Dawson TM, Dawson VL, Arrowsmith CH, and Truant R
Subjects: Humans, DNA Damage, Neurons metabolism, Induced Pluripotent Stem Cells metabolism, Fibroblasts metabolism, DNA Repair, Huntington Disease metabolism, Huntington Disease genetics, Huntington Disease pathology, Huntingtin Protein metabolism, Huntingtin Protein genetics, Poly Adenosine Diphosphate Ribose metabolism, Signal Transduction
Abstract: Huntington disease (HD) is a genetic neurodegenerative disease caused by cytosine, adenine, guanine (CAG) expansion in the Huntingtin ( HTT ) gene, translating to an expanded polyglutamine tract in the HTT protein. Age at disease onset correlates to CAG repeat length but varies by decades between individuals with identical repeat lengths. Genome-wide association studies link HD modification to DNA repair and mitochondrial health pathways. Clinical studies show elevated DNA damage in HD, even at the premanifest stage. A major DNA repair node influencing neurodegenerative disease is the PARP pathway. Accumulation of poly adenosine diphosphate (ADP)-ribose (PAR) has been implicated in Alzheimer and Parkinson diseases, as well as cerebellar ataxia. We report that HD mutation carriers have lower cerebrospinal fluid PAR levels than healthy controls, starting at the premanifest stage. Human HD induced pluripotent stem cell-derived neurons and patient-derived fibroblasts have diminished PAR response in the context of elevated DNA damage. We have defined a PAR-binding motif in HTT, detected HTT complexed with PARylated proteins in human cells during stress, and localized HTT to mitotic chromosomes upon inhibition of PAR degradation. Direct HTT PAR binding was measured by fluorescence polarization and visualized by atomic force microscopy at the single molecule level. While wild-type and mutant HTT did not differ in their PAR binding ability, purified wild-type HTT protein increased in vitro PARP1 activity while mutant HTT did not. These results provide insight into an early molecular mechanism of HD, suggesting possible targets for the design of early preventive therapies., Competing Interests: Competing interests statement:E.J.W. reports consultancy/ advisory board memberships with Annexon, Remix Therapeutics, Hoffman La Roche Ltd., Ionis Pharmaceuticals, PTC Therapeutics, Takeda, Teitur Trophics, Triplet Therapeutics and Vico Therapeutics. All honoraria for these consultancies were paid through the offices of UCL Consultants Ltd., a wholly owned subsidiary of University College London. F.B.R. is a Medpace UK Ltd. employee and was a University College London employee during the conduct of this study. F.B.R. has provided consultancy services to GLG and F. Hoffmann-La Roche Ltd. L.M.B. currently holds consultancy contracts with Annexon Biosciences, Remix Therapeutics, and LoQus23 Therapeutics Ltd. via UCL Consultants Ltd. R.T. has past consultancy with Novartis AG, PTC Therapeutics and Mitokinin LLC.
Published: 2024
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31. Chemical coverage of human biological pathways.

Author: Kwak HA, Liu L, Tredup C, Röhm S, Prinos P, Böttcher J, and Schapira M
Subjects: Humans, Precision Medicine methods, Proteome, Signal Transduction drug effects, Drug Discovery methods
Abstract: Chemical probes and chemogenomic compounds are valuable tools to link gene to phenotype, explore human biology, and uncover novel targets for precision medicine. The mission of the Target 2035 initiative is to discover chemical tools for all human proteins by the year 2035. Here, we draw a landscape of the current chemical coverage of human biological pathways. Although available chemical tools target only 3% of the human proteome, they already cover 53% of human biological pathways and represent a versatile toolkit to dissect a vast portion of human biology. Pathways targeted by existing drugs may be enriched in unknown but valid drug targets and could be prioritized in future Target 2035 efforts., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Published: 2024
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32. Unlocking the potential: unveiling tyrphostins with Michael-reactive cyanoacrylate motif as promising inhibitors of human 5-lipoxygenase.

Author: Molitor M, Menge A, Mandel S, George S, Müller S, Knapp S, Hofmann B, Steinhilber D, and Häfner AK
Abstract: Human 5-lipoxygenase (5-LO) is the key enzyme in the biosynthesis of leukotrienes, mediators of the innate immune system that also play an important role in inflammatory diseases and cancer. In this study, we present compounds, containing a Michael-reactive cyanoacrylate moiety as potent inhibitors of 5-LO. Representatives of the tyrosine kinase inhibitor family called tyrphostins, structurally related to known 5-LO inhibitors, were screened for their 5-LO inhibitory properties using recombinant human 5-LO, intact human PMNL (polymorphonuclear leukocytes), and PMNL homogenates. Their mode of action was characterized by the addition of glutathione, using a fourfold cysteine 5-LO mutant and mass spectrometry analysis. SAR studies revealed several members of the tyrphostin family containing a Michael-reactive cyanoacrylate to efficiently inhibit 5-LO. We identified degrasyn (IC 50 0.11 µM), tyrphostin A9 (IC 50 0.8 µM), AG879 (IC 50 78 nM), and AG556 (IC 50 64 nM) as potent 5-LO inhibitors. Mass spectrometry analysis revealed that degrasyn and AG556 covalently bound to up to four cysteines, including C416 and/or C418 which surround the substrate entry site. Furthermore, the 5-LO inhibitory effect of degrasyn was remarkably impaired by the addition of glutathione or by the mutation of cysteines to serines at the surface of 5-LO. We successfully identified several tyrphostins as potent inhibitors of human 5-LO. Degrasyn and AG556 were able to covalently bind to 5-LO via their cyanoacrylate moiety. This provides a promising mechanism for targeting 5-LO by Michael acceptors, leading to new therapeutic opportunities in the field of inflammation and cancer., (© 2024. The Author(s).)
Published: 2024
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33. Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors of Chikungunya nsP2 Cysteine Protease with Antialphavirus Activity.

Author: Ghoshal A, Asressu KH, Hossain MA, Brown PJ, Nandakumar M, Vala A, Merten EM, Sears JD, Law I, Burdick JE, Morales NL, Perveen S, Pearce KH, Popov KI, Moorman NJ, Heise MT, and Willson TM
Subjects: Structure-Activity Relationship, Cysteine Proteinase Inhibitors pharmacology, Cysteine Proteinase Inhibitors chemical synthesis, Cysteine Proteinase Inhibitors chemistry, Humans, Animals, Virus Replication drug effects, Antiviral Agents pharmacology, Antiviral Agents chemistry, Antiviral Agents chemical synthesis, Sulfones pharmacology, Sulfones chemistry, Sulfones chemical synthesis, Chikungunya virus drug effects, Chikungunya virus enzymology, Cysteine Endopeptidases metabolism
Abstract: Despite their widespread impact on human health, there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 ( 1a ) is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad-spectrum antiviral activity. Analogs of 1a that varied each of the three regions of the molecule were synthesized to establish structure-activity relationships for the inhibition of Chikungunya (CHIKV) nsP2 protease and viral replication. The vinyl sulfone covalent warhead was highly sensitive to modifications. However, alterations to the core five-membered heterocycle and aryl substituent were well tolerated. The 5-(2,5-dimethoxyphenyl)pyrazole ( 1o ) and 4-cyanopyrazole ( 8d ) analogs exhibited k inact / K i ratios >9000 M -1 s -1 . 3-Arylisoxazole ( 10 ) was identified as an isosteric replacement for the five-membered heterocycle, which circumvented the intramolecular cyclization of pyrazole-based inhibitors like 1a . A ligand-based model of the enzyme active site was developed to aid the design of nsP2 protease inhibitors as potential therapeutics against alphaviruses.
Published: 2024
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34. PRMT1 inhibition perturbs RNA metabolism and induces DNA damage in clear cell renal cell carcinoma.

Author: Walton J, Ng ASN, Arevalo K, Apostoli A, Meens J, Karamboulas C, St-Germain J, Prinos P, Dmytryshyn J, Chen E, Arrowsmith CH, Raught B, and Ailles L
Subjects: Animals, Humans, Mice, Cell Line, Tumor, DNA Repair drug effects, Epigenesis, Genetic drug effects, Gene Expression Regulation, Neoplastic drug effects, Proteomics, RNA metabolism, RNA genetics, Male, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell metabolism, Carcinoma, Renal Cell pathology, DNA Damage drug effects, Kidney Neoplasms genetics, Kidney Neoplasms metabolism, Kidney Neoplasms drug therapy, Kidney Neoplasms pathology, Protein-Arginine N-Methyltransferases metabolism, Protein-Arginine N-Methyltransferases antagonists & inhibitors, Protein-Arginine N-Methyltransferases genetics, Repressor Proteins metabolism, Repressor Proteins genetics, Repressor Proteins antagonists & inhibitors
Abstract: In addition to the ubiquitous loss of the VHL gene in clear cell renal cell carcinoma (ccRCC), co-deletions of chromatin-regulating genes are common drivers of tumorigenesis, suggesting potential vulnerability to epigenetic manipulation. A library of chemical probes targeting a spectrum of epigenetic regulators is screened using a panel of ccRCC models. MS023, a type I protein arginine methyltransferase (PRMT) inhibitor, is identified as an antitumorigenic agent. Individual knockdowns indicate PRMT1 as the specific critical dependency for cancer growth. Further analyses demonstrate impairments to cell cycle and DNA damage repair pathways upon MS023 treatment or PRMT1 knockdown. PRMT1-specific proteomics reveals an interactome rich in RNA binding proteins and further investigation indicates significant widespread disruptions in mRNA metabolism with both MS023 treatment and PRMT1 knockdown, resulting in R-loop accumulation and DNA damage over time. Our data supports PRMT1 as a target in ccRCC and informs a mechanism-based strategy for translational development., (© 2024. The Author(s).)
Published: 2024
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35. Activation of parkin by a molecular glue.

Author: Sauvé V, Stefan E, Croteau N, Goiran T, Fakih R, Bansal N, Hadzipasic A, Fang J, Murugan P, Chen S, Fon EA, Hirst WD, Silvian LF, Trempe JF, and Gehring K
Subjects: Humans, Protein Kinases metabolism, Protein Kinases genetics, Protein Kinases chemistry, Crystallography, X-Ray, Mutation, Phosphorylation, Allosteric Regulation, Mitophagy drug effects, Ubiquitin metabolism, Models, Molecular, Protein Binding, HEK293 Cells, Ubiquitin-Protein Ligases metabolism, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases chemistry, Parkinson Disease metabolism, Parkinson Disease drug therapy, Parkinson Disease genetics, Parkinson Disease pathology, Ubiquitination
Abstract: Mutations in parkin and PINK1 cause early-onset Parkinson's disease (EOPD). The ubiquitin ligase parkin is recruited to damaged mitochondria and activated by PINK1, a kinase that phosphorylates ubiquitin and the ubiquitin-like domain of parkin. Activated phospho-parkin then ubiquitinates mitochondrial proteins to target the damaged organelle for degradation. Here, we present the mechanism of activation of a new class of small molecule allosteric modulators that enhance parkin activity. The compounds act as molecular glues to enhance the ability of phospho-ubiquitin (pUb) to activate parkin. Ubiquitination assays and isothermal titration calorimetry with the most active compound (BIO-2007817) identify the mechanism of action. We present the crystal structure of a closely related compound (BIO-1975900) bound to a complex of parkin and two pUb molecules. The compound binds next to pUb on RING0 and contacts both proteins. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) experiments confirm that activation occurs through release of the catalytic Rcat domain. In organello and mitophagy assays demonstrate that BIO-2007817 partially rescues the activity of parkin EOPD mutants, R42P and V56E, offering a basis for the design of activators as therapeutics for Parkinson's disease., (© 2024. The Author(s).)
Published: 2024
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36. Elimination of mutant SWI/SNF complexes by protein quality control: new opportunities targeting aggressive rhabdoid tumours.

Author: Krämer A and Knapp S
Subjects: Humans, Chromosomal Proteins, Non-Histone genetics, Chromosomal Proteins, Non-Histone metabolism, Mutation, SMARCB1 Protein genetics, SMARCB1 Protein metabolism, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Rhabdoid Tumor genetics, Rhabdoid Tumor pathology, Transcription Factors genetics, Transcription Factors metabolism
Published: 2024
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37. A guide to selecting high-performing antibodies for CSNK2A1 (UniProt ID: P68400) for use in western blot, immunoprecipitation and immunofluorescence.

Author: Ayoubi R, Fotouhi M, Alende C, Ruíz Moleón V, Southern K, and Laflamme C
Subjects: Humans, HEK293 Cells, Immunoprecipitation methods, Casein Kinase II immunology, Casein Kinase II metabolism, Fluorescent Antibody Technique methods, Blotting, Western, Antibodies immunology
Abstract: Casein kinase II subunit alpha (CSNK2A1), a serine/threonine kinase, phosphorylates multiple protein substrates and is involved in diverse cellular and biological processes. Implicated in various human diseases, high-performing antibodies would help evaluate its potential as a therapeutic target and benefit the scientific community. In this study, we have characterized ten CSNK2A1 commercial antibodies for western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a larger, collaborative initiative seeking to address antibody reproducibility issues by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs., Competing Interests: Competing interests: For this project, the laboratory of Peter McPherson developed partnerships with high-quality antibody manufacturers and knockout cell line providers. The partners provide antibodies and knockout cell lines to the McPherson laboratory at no cost. These partners include: - Abcam -Aviva Systems Biology -Bio Techne -Cell Signalling Technology -Developmental Studies Hybridoma Bank -GeneTex -Horizon Discovery -Proteintech -Synaptic Systems -Thermo Fisher Scientific., (Copyright: © 2024 Ayoubi R et al.)
Published: 2024
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38. Identification of high-performing antibodies for SPARC-related modular calcium-binding protein 1 (SMOC-1) for use in Western Blot and immunoprecipitation.

Author: Ayoubi R, González Bolívar S, Nicouleau M, Southern K, and Laflamme C
Subjects: Humans, Calcium-Binding Proteins immunology, Animals, Alzheimer Disease diagnosis, Immunoprecipitation methods, Blotting, Western, Antibodies immunology
Abstract: SPARC-related modular calcium-binding protein 1, otherwise known as SMOC-1, is a secreted glycoprotein involved in various cell biological processes including cell-matrix interactions, osteoblast differentiation, embryonic development, and homeostasis. SMOC-1 was found to be elevated in asymptomatic Alzheimer's disease (AD) patient cortex as well as being enriched in amyloid plaques and in AD patientcerebrospinal fluid, arguing for SMOC-1 as a promising biomarker for AD. Having access to high-quality SMOC-1 antibodies is crucial for the scientific community. It can ensure the consistency and reliability of SMOC-1 research, and further the exploration of its potential as both a therapeutic target or diagnostic marker.. In this study, we characterized seven SMOC-1 commercial antibodies for Western blot and immunoprecipitation, using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified successful antibodies in the tested applications and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs., Competing Interests: Competing interests: For this project, the laboratory of Peter McPherson developed partnerships with high-quality antibody manufacturers and knockout cell line providers. The partners provide antibodies and knockout cell lines to the McPherson laboratory at no cost. These partners include: - Abcam -Aviva Systems Biology -Bio Techne -Cell Signalling Technology -Developmental Studies Hybridoma Bank -GeneTex – Horizon Discovery – Proteintech – Synaptic Systems -Thermo Fisher Scientific., (Copyright: © 2024 Ayoubi R et al.)
Published: 2024
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39. Strategic Fluorination to Achieve a Potent, Selective, Metabolically Stable, and Orally Bioavailable Inhibitor of CSNK2.

Author: Ong HW, Yang X, Smith JL, Taft-Benz S, Howell S, Dickmander RJ, Havener TM, Sanders MK, Brown JW, Couñago RM, Chang E, Krämer A, Moorman NJ, Heise M, Axtman AD, Drewry DH, and Willson TM
Subjects: Humans, Animals, Biological Availability, Administration, Oral, Pyrimidines chemistry, Pyrimidines pharmacokinetics, Pyrimidines pharmacology, Structure-Activity Relationship, SARS-CoV-2 drug effects, Casein Kinase II antagonists & inhibitors, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors pharmacokinetics, Antiviral Agents chemistry, Antiviral Agents pharmacology, Antiviral Agents pharmacokinetics, Halogenation
Abstract: The host kinase casein kinase 2 (CSNK2) has been proposed to be an antiviral target against β-coronaviral infection. To pharmacologically validate CSNK2 as a drug target in vivo, potent and selective CSNK2 inhibitors with good pharmacokinetic properties are required. Inhibitors based on the pyrazolo[1,5- a ]pyrimidine scaffold possess outstanding potency and selectivity for CSNK2, but bioavailability and metabolic stability are often challenging. By strategically installing a fluorine atom on an electron-rich phenyl ring of a previously characterized inhibitor 1 , we discovered compound 2 as a promising lead compound with improved in vivo metabolic stability. Compound 2 maintained excellent cellular potency against CSNK2, submicromolar antiviral potency, and favorable solubility, and was remarkably selective for CSNK2 when screened against 192 kinases across the human kinome. We additionally present a co-crystal structure to support its on-target binding mode. In vivo, compound 2 was orally bioavailable, and demonstrated modest and transient inhibition of CSNK2, although antiviral activity was not observed, possibly attributed to its lack of prolonged CSNK2 inhibition.
Published: 2024
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40. A chemical probe to modulate human GID4 Pro/N-degron interactions.

Author: Owens DDG, Maitland MER, Khalili Yazdi A, Song X, Reber V, Schwalm MP, Machado RAC, Bauer N, Wang X, Szewczyk MM, Dong C, Dong A, Loppnau P, Calabrese MF, Dowling MS, Lee J, Montgomery JI, O'Connell TN, Subramanyam C, Wang F, Adamson EC, Schapira M, Gstaiger M, Knapp S, Vedadi M, Min J, Lajoie GA, Barsyte-Lovejoy D, Owen DR, Schild-Poulter C, and Arrowsmith CH
Subjects: Humans, Proteolysis, HEK293 Cells, Molecular Probes chemistry, Molecular Probes metabolism, DEAD-box RNA Helicases metabolism, Ubiquitin-Protein Ligases metabolism, Degrons, Receptors, Interleukin-17, Protein Binding
Abstract: The C-terminal to LisH (CTLH) complex is a ubiquitin ligase complex that recognizes substrates with Pro/N-degrons via its substrate receptor Glucose-Induced Degradation 4 (GID4), but its function and substrates in humans remain unclear. Here, we report PFI-7, a potent, selective and cell-active chemical probe that antagonizes Pro/N-degron binding to human GID4. Use of PFI-7 in proximity-dependent biotinylation and quantitative proteomics enabled the identification of GID4 interactors and GID4-regulated proteins. GID4 interactors are enriched for nucleolar proteins, including the Pro/N-degron-containing RNA helicases DDX21 and DDX50. We also identified a distinct subset of proteins whose cellular levels are regulated by GID4 including HMGCS1, a Pro/N-degron-containing metabolic enzyme. These data reveal human GID4 Pro/N-degron targets regulated through a combination of degradative and nondegradative functions. Going forward, PFI-7 will be a valuable research tool for investigating CTLH complex biology and facilitating development of targeted protein degradation strategies that highjack CTLH E3 ligase activity., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Published: 2024
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41. Autoinhibition of ubiquitin-specific protease 8: Insights into domain interactions and mechanisms of regulation.

Author: Caba C, Black M, Liu Y, DaDalt AA, Mallare J, Fan L, Harding RJ, Wang YX, Vacratsis PO, Huang R, Zhuang Z, and Tong Y
Abstract: Ubiquitin-specific proteases (USPs) are a family of multi-domain deubiquitinases (DUBs) with variable architectures, some containing regulatory auxiliary domains. Among the USP family, all occurrences of intramolecular regulation presently known are autoactivating. USP8 remains the sole exception as its putative WW-like domain, conserved only in vertebrate orthologs, is autoinhibitory. Here, we present a comprehensive structure-function analysis describing the autoinhibition of USP8 and provide evidence of the physical interaction between the WW-like and catalytic domains. The solution structure of full-length USP8 reveals an extended, monomeric conformation. Coupled with DUB assays, the WW-like domain is confirmed to be the minimal autoinhibitory unit. Strikingly, autoinhibition is only observed with the WW-like domain in cis and depends on the length of the linker tethering it to the catalytic domain. Modeling of the WW:CD complex structure and mutagenesis of interface residues suggests a novel binding site in the S1 pocket. To investigate the interplay between phosphorylation and USP8 autoinhibition, we identify AMP-activated protein kinase as a highly selective modifier of S718 in the 14-3-3 binding motif. We show that 14-3-3γ binding to phosphorylated USP8 potentiates autoinhibition in a WW-like domain-dependent manner by stabilizing an autoinhibited conformation. These findings provide mechanistic details on the autoregulation of USP8 and shed light on its evolutionary significance., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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42. Inhibition of bromodomain and extra-terminal proteins targets constitutively active NFκB and STAT signaling in lymphoma and influences the expression of the antiapoptotic proteins BCL2A1 and c-MYC.

Author: Pieper NM, Schnell J, Bruecher D, Knapp S, and Vogler M
Subjects: Humans, Cell Line, Tumor, Gene Expression Regulation, Neoplastic drug effects, Apoptosis drug effects, Bromodomain Containing Proteins, Proteins, Minor Histocompatibility Antigens, Proto-Oncogene Proteins c-bcl-2 metabolism, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-myc metabolism, Proto-Oncogene Proteins c-myc genetics, Signal Transduction drug effects, NF-kappa B metabolism, Lymphoma, Large B-Cell, Diffuse metabolism, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse pathology
Abstract: The antiapoptotic protein BCL2A1 is highly, but very heterogeneously expressed in Diffuse Large B-cell Lymphoma (DLBCL). Particularly in the context of resistance to current therapies, BCL2A1 appears to play an important role in protecting cancer cells from the induction of cell death. Reducing BCL2A1 levels may have therapeutic potential, however, no specific inhibitor is currently available. In this study, we hypothesized that the signaling network regulated by epigenetic readers may regulate the transcription of BCL2A1 and hence that inhibition of Bromodomain and Extra-Terminal (BET) proteins may reduce BCL2A1 expression thus leading to cell death in DLBCL cell lines. We found that the mechanisms of action of acetyl-lysine competitive BET inhibitors are different from those of proteolysis targeting chimeras (PROTACs) that induce the degradation of BET proteins. Both classes of BETi reduced the expression of BCL2A1 which coincided with a marked downregulation of c-MYC. Mechanistically, BET inhibition attenuated the constitutively active canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB) signaling pathway and inhibited p65 activation. Furthermore, signal transducer of activated transcription (STAT) signaling was reduced by inhibiting BET proteins, targeting another pathway that is often constitutively active in DLBCL. Both pathways were also inhibited by the IκB kinase inhibitor TPCA-1, resulting in decreased BCL2A1 and c-MYC expression. Taken together, our study highlights a novel complex regulatory network that links BET proteins to both NFκB and STAT survival signaling pathways controlling both BCL2A1 and c-MYC expression in DLBCL., (© 2024. The Author(s).)
Published: 2024
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43. A chemical screen identifies PRMT5 as a therapeutic vulnerability for paclitaxel-resistant triple-negative breast cancer.

Author: Zhang K, Wei J, Zhang S, Fei L, Guo L, Liu X, Ji Y, Chen W, Ciamponi FE, Chen W, Li M, Zhai J, Fu T, Massirer KB, Yu Y, Lupien M, Wei Y, Arrowsmith CH, Wu Q, and Tan W
Abstract: Paclitaxel-resistant triple negative breast cancer (TNBC) remains one of the most challenging breast cancers to treat. Here, using an epigenetic chemical probe screen, we uncover an acquired vulnerability of paclitaxel-resistant TNBC cells to protein arginine methyltransferases (PRMTs) inhibition. Analysis of cell lines and in-house clinical samples demonstrates that resistant cells evade paclitaxel killing through stabilizing mitotic chromatin assembly. Genetic or pharmacologic inhibition of PRMT5 alters RNA splicing, particularly intron retention of aurora kinases B (AURKB), leading to a decrease in protein expression, and finally results in selective mitosis catastrophe in paclitaxel-resistant cells. In addition, type I PRMT inhibition synergies with PRMT5 inhibition in suppressing tumor growth of drug-resistant cells through augmenting perturbation of AURKB-mediated mitotic signaling pathway. These findings are fully recapitulated in a patient-derived xenograft (PDX) model generated from a paclitaxel-resistant TNBC patient, providing the rationale for targeting PRMTs in paclitaxel-resistant TNBC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
Published: 2024
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44. Screening of a kinase inhibitor library identified novel targetable kinase pathways in triple-negative breast cancer.

Author: Rinderle CH, Baker CV, Lagarde CB, Nguyen K, Al-Ghadban S, Matossian MD, Hoang VT, Martin EC, Collins-Burow BM, Ali S, Drewry DH, Burow ME, and Bunnell BA
Abstract: Triple-negative breast cancer (TNBC) is a highly invasive breast cancer subtype that is challenging to treat due to inherent heterogeneity and absence of estrogen, progesterone, and human epidermal growth factor 2 receptors. Kinase signaling networks drive cancer growth and development, and kinase inhibitors are promising anti-cancer strategies in diverse cancer subtypes. Kinase inhibitor screens are an efficient, valuable means of identifying compounds that suppress cancer cell growth in vitro, facilitating the identification of kinase vulnerabilities to target therapeutically. The Kinase Chemogenomic Set is a well-annotated library of 187 kinase inhibitor compounds that indexes 215 kinases of the 518 in the known human kinome representing various kinase networks and signaling pathways, several of which are understudied. Our screen revealed 14 kinase inhibitor compounds effectively inhibited TNBC cell growth and proliferation. Upon further testing, three compounds, THZ531, THZ1, and PFE-PKIS 29, had the most significant and consistent effects across a range of TNBC cell lines. These cyclin-dependent kinase (CDK)12/CDK13, CDK7, and phosphoinositide 3-kinase inhibitors, respectively, decreased metabolic activity in TNBC cell lines and promote a gene expression profile consistent with the reversal of the epithelial-to-mesenchymal transition, indicating these kinase networks potentially mediate metastatic behavior. These data identified novel kinase targets and kinase signaling pathways that drive metastasis in TNBC., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)
Published: 2024
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45. Antibody characterization is critical to enhance reproducibility in biomedical research.

Author: Kahn RA, Virk H, Laflamme C, Houston DW, Polinski NK, Meijers R, Levey AI, Saper CB, Errington TM, Turn RE, Bandrowski A, Trimmer JS, Rego M, Freedman LP, Ferrara F, Bradbury ARM, Cable H, and Longworth S
Subjects: Reproducibility of Results, Humans, Animals, Biomedical Research, Antibodies
Abstract: Antibodies are used in many areas of biomedical and clinical research, but many of these antibodies have not been adequately characterized, which casts doubt on the results reported in many scientific papers. This problem is compounded by a lack of suitable control experiments in many studies. In this article we review the history of the 'antibody characterization crisis', and we document efforts and initiatives to address the problem, notably for antibodies that target human proteins. We also present recommendations for a range of stakeholders - researchers, universities, journals, antibody vendors and repositories, scientific societies and funders - to increase the reproducibility of studies that rely on antibodies., Competing Interests: RK, HV, CL, DH, NP, RM, AL, CS, TE, RT, JT, LF, FF, AB, SL No competing interests declared, AB Co-founder and serving as CEO of SciCrunch Inc, a company that works with publishers to improve the scientific literature; the terms of this agreement have been approved by the COI office at the University of California at San Diego, MR Employed by Addgene, a company that may be affected financially by the opinions reported in this article, HC Employed by Abcam, a for-profit company that sells antibodies and which may be affected financially by the opinions reported in this article, (© 2024, Kahn et al.)
Published: 2024
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46. A guide to selecting high-performing antibodies for Huntingtin (UniProt ID: P42858) for use in western blot, immunoprecipitation, and immunofluorescence.

Author: Fanti R, Ayoubi R, Alende C, Fotouhi M, González Bolívar S, Chandrasekaran R, Southern K, Edwards AM, Harding RJ, and Laflamme C
Subjects: Humans, Animals, Huntington Disease immunology, Huntington Disease diagnosis, Huntington Disease genetics, HEK293 Cells, Huntingtin Protein genetics, Huntingtin Protein immunology, Immunoprecipitation methods, Fluorescent Antibody Technique methods, Blotting, Western, Antibodies immunology
Abstract: Huntingtin encodes a 3144 amino acid protein, with a polyglutamine repeat tract at the N-terminus. Expansion of this repeat tract above a pathogenic threshold of 36 repeats is the causative mutation of Huntington's disease, a neurodegenerative disorder characterized by loss of striatal neurons. Here we have characterized twenty Huntingtin commercial antibodies for western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a larger, collaborative initiative seeking to address antibody reproducibility issues by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs., Competing Interests: Competing interests: For this project, the laboratory of Peter McPherson developed partnerships with high-quality antibody manufacturers and knockout cell line providers. The partners provide antibodies and knockout cell lines to the McPherson laboratory at no cost. These partners include: Abcam, Aviva Systems Biology, Bio-Techne, Cell Signalling Technology, Developmental Studies Hybridoma Bank, GeneTex, Horizon Discovery, Proteintech, Synaptic Systems, Thermo Fisher Scientific., (Copyright: © 2024 Fanti R et al.)
Published: 2024
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47. Quantitative Hydrogen-Deuterium Exchange Mass Spectrometry for Simultaneous Structural Characterization and Affinity Indexing of Single Target Drug Candidate Libraries.

Author: Wolf E, Herasymenko O, Kutera M, Lento C, Arrowsmith C, Ackloo S, and Wilson D
Subjects: Humans, Small Molecule Libraries chemistry, Small Molecule Libraries metabolism, Hydrogen Deuterium Exchange-Mass Spectrometry methods, Surface Plasmon Resonance methods
Abstract: Hydrogen-deuterium eXchange mass spectrometry (HDX-MS) is increasingly used in drug development to locate binding sites and to identify allosteric effects in drug/target interactions. However, the potential of this technique to quantitatively analyze drug candidate libraries remains largely unexplored. Here, a collection of 13 WDR5-targeting small molecules with surface plasmon resonance (SPR) dissociation coefficients ( K D ) ranging from 20 nM to ∼116 μM were characterized using differential HDX-MS (ΔHDX-MS). Conventional qualitative analysis of the ΔHDX-MS data set revealed the binding interfaces for all compounds and allosteric effects where present. We then demonstrated that ΔHDX-MS signal-to-noise (S/N) not only can rank library-relative affinity but also can accurately predict K D from a calibration curve constructed from high-quality SPR data. Three methods for S/N calculation are explored, each suitable for libraries with different characteristics. Our results demonstrate the potential for ΔHDX-MS use in drug candidate library affinity validation and/or determination while simultaneously characterizing structure.
Published: 2024
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48. Benchmarking Methods for PROTAC Ternary Complex Structure Prediction.

Author: Rovers E and Schapira M
Subjects: Proteolysis, Protein Conformation, Proteins chemistry, Ubiquitin-Protein Ligases chemistry, Ubiquitin-Protein Ligases metabolism, Benchmarking, Molecular Dynamics Simulation
Abstract: Proteolysis targeting chimeras (PROTACs) are bifunctional compounds that recruit an E3 ligase to a target protein to induce ubiquitination and degradation of the target. Rational optimization of PROTAC requires a structural model of the ternary complex. In the absence of an experimental structure, computational tools have emerged that attempt to predict PROTAC ternary complexes. Here, we systematically benchmark three commonly used tools: PRosettaC, MOE, and ICM. We find that these PROTAC-focused methods produce an array of ternary complex structures, including some that are observed experimentally, but also many that significantly deviate from the crystal structure. Molecular dynamics simulations show that PROTAC complexes may exist in a multiplicity of configurational states and question the use of experimentally observed structures as a reference for accurate predictions. The pioneering computational tools benchmarked here highlight the promises and challenges in the field and may be more valuable when guided by clear structural and biophysical data. The benchmarking data set that we provide may also be valuable for evaluating other and future computational tools for ternary complex modeling.
Published: 2024
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49. Discovery of Two Highly Selective Structurally Orthogonal Chemical Probes for Activin Receptor-like Kinases 1 and 2.

Author: Němec V, Remeš M, Beňovský P, Böck MC, Šranková E, Wong JF, Cros J, Williams E, Tse LH, Smil D, Ensan D, Isaac MB, Al-Awar R, Gomolková R, Ursachi VC, Fafílek B, Kahounová Z, Víchová R, Vacek O, Berger BT, Wells CI, Corona CR, Vasta JD, Robers MB, Krejci P, Souček K, Bullock AN, Knapp S, and Paruch K
Subjects: Animals, Humans, Mice, Activin Receptors, Type I antagonists & inhibitors, Activin Receptors, Type I metabolism, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors chemistry, Structure-Activity Relationship, Signal Transduction drug effects, Drug Discovery, Molecular Probes chemistry, Bone Morphogenetic Proteins metabolism, Pyrazoles chemistry, Pyrazoles pharmacology, Pyrazoles chemical synthesis, Activin Receptors, Type II metabolism, Activin Receptors, Type II antagonists & inhibitors
Abstract: Activin receptor-like kinases 1-7 (ALK1-7) regulate a complex network of SMAD-independent as well as SMAD-dependent signaling pathways. One of the widely used inhibitors for functional investigations of these processes, in particular for bone morphogenetic protein (BMP) signaling, is LDN-193189 . However, LDN-193189 has insufficient kinome-wide selectivity complicating its use in cellular target validation assays. Herein, we report the identification and comprehensive characterization of two chemically distinct highly selective inhibitors of ALK1 and ALK2, M4K2234 and MU1700 , along with their negative controls. We show that both MU1700 and M4K2234 efficiently block the BMP pathway via selective in cellulo inhibition of ALK1/2 kinases and exhibit favorable in vivo profiles in mice. MU1700 is highly brain penetrant and shows remarkably high accumulation in the brain. These high-quality orthogonal chemical probes offer the selectivity required to become widely used tools for in vitro and in vivo investigation of BMP signaling.
Published: 2024
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50. Back-Pocket Optimization of 2-Aminopyrimidine-Based Macrocycles Leads to Potent EPHA2/GAK Kinase Inhibitors.

Author: Gerninghaus J, Zhubi R, Krämer A, Karim M, Tran DHN, Joerger AC, Schreiber C, Berger LM, Berger BT, Ehret TAL, Elson L, Lenz C, Saxena K, Müller S, Einav S, Knapp S, and Hanke T
Subjects: Humans, Cell Line, Tumor, Crystallography, X-Ray, Dengue Virus drug effects, Intracellular Signaling Peptides and Proteins, Macrocyclic Compounds chemistry, Macrocyclic Compounds pharmacology, Macrocyclic Compounds chemical synthesis, Models, Molecular, Protein Serine-Threonine Kinases, Structure-Activity Relationship, Morpholines, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors chemical synthesis, Pyrimidines chemistry, Pyrimidines pharmacology, Pyrimidines chemical synthesis, Receptor, EphA2 antagonists & inhibitors, Receptor, EphA2 metabolism
Abstract: Macrocyclization of acyclic compounds is a powerful strategy for improving inhibitor potency and selectivity. Here we have optimized 2-aminopyrimidine-based macrocycles to use these compounds as chemical tools for the ephrin kinase family. Starting with a promiscuous macrocyclic inhibitor, 6 , we performed a structure-guided activity relationship and selectivity study using a panel of over 100 kinases. The crystal structure of EPHA2 in complex with the developed macrocycle 23 provided a basis for further optimization by specifically targeting the back pocket, resulting in compound 55 , a potent inhibitor of EPHA2/A4 and GAK. Subsequent front-pocket derivatization resulted in an interesting in cellulo selectivity profile, favoring EPHA4 over the other ephrin receptor kinase family members. The dual EPHA2/A4 and GAK inhibitor 55 prevented dengue virus infection of Huh7 liver cells. However, further investigations are needed to determine whether this was a compound-specific effect or target-related.
Published: 2024
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