36 results on '"Chebaro Y"'
Search Results
2. The molecular mechanisms underlying the ERα-36-mediated signaling in breast cancer
- Author
-
Omarjee, S., primary, Jacquemetton, J., additional, Poulard, C., additional, Rochel, N., additional, Dejaegere, A., additional, Chebaro, Y., additional, Treilleux, I., additional, Marangoni, E., additional, Corbo, L., additional, and Le Romancer, M., additional
- Published
- 2016
- Full Text
- View/download PDF
3. Exploring the First Steps of Aβ16-22 Protofibril Disassembly by N-Methylated Inhibitors
- Author
-
Chebaro, Y. and Derreumaux, Ph.
- Subjects
ddc:004 - Published
- 2008
4. Substitutions at residue 211 in the prion protein drive a switch between CJD and GSS syndrome, a new mechanism governing inherited neurodegenerative disorders
- Author
-
Peoc'h, K., primary, Levavasseur, E., additional, Delmont, E., additional, De Simone, A., additional, Laffont-Proust, I., additional, Privat, N., additional, Chebaro, Y., additional, Chapuis, C., additional, Bedoucha, P., additional, Brandel, J.-P., additional, Laquerriere, A., additional, Kemeny, J.-L., additional, Hauw, J.-J., additional, Borg, M., additional, Rezaei, H., additional, Derreumaux, P., additional, Laplanche, J.-L., additional, and Haik, S., additional
- Published
- 2014
- Full Text
- View/download PDF
5. 772 - The molecular mechanisms underlying the ERα-36-mediated signaling in breast cancer
- Author
-
Omarjee, S., Jacquemetton, J., Poulard, C., Rochel, N., Dejaegere, A., Chebaro, Y., Treilleux, I., Marangoni, E., Corbo, L., and Le Romancer, M.
- Published
- 2016
- Full Text
- View/download PDF
6. The molecular mechanisms underlying the ERα-36-mediated signaling in breast cancer
- Author
-
Omarjee, S, Jacquemetton, J, Poulard, C, Rochel, N, Dejaegere, A, Chebaro, Y, Treilleux, I, Marangoni, E, Corbo, L, and Romancer, M Le
- Abstract
Alterations in estrogen-mediated cellular signaling have largely been implicated in the pathogenesis of breast cancer. Here, we investigated the signaling regulation of a splice variant of the estrogen receptor, namely estrogen receptor (ERα-36), associated with a poor prognosis in breast cancers. Coupling in vitro and in vivo approaches we determined the precise sequential molecular events of a new estrogen signaling network in an ERα-negative cell line and in an original patient-derived xenograft. After estrogen treatment, ERα-36 rapidly associates with Src at the level of the plasma membrane, initiating downstream cascades, including MEK1/ERK activation and paxillin phosphorylation on S126, which in turn triggers a higher expression of cyclin D1. Of note, the direct binding of ERα-36 to ERK2 prevents its dephosphorylation by MKP3 and enhances the downstream signaling. These findings improve our understanding of the regulation of non-genomic estrogen signaling and open new avenues for personalized therapeutic approaches targeting Src or MEK in ERα-36-positive patients.
- Published
- 2017
- Full Text
- View/download PDF
7. Allostery in Its Many Disguises: From Theory to Applications
- Author
-
Yassmine Chebaro, Annick Dejaegere, Ruth Nussinov, Rebecca C. Wade, Simone Orioli, Jocelyne Vreede, Riccardo Ravasio, Paraskevi Gkeka, Jing Li, Gerhard Stock, Chung-Jung Tsai, Ivet Bahar, Emanuele Paci, Pietro Faccioli, Joanna Panecka-Hofman, John Karanicolas, Peter G. Bolhuis, Jean-Pierre Changeux, Shoshana J. Wodak, Masha Y. Niv, Antonella Di Pizio, Giulia Palermo, Roland H. Stote, Tom McLeish, Matthieu Wyart, Carolina Brito, Peter Hamm, J. Andrew McCammon, Vincent J. Hilser, Amnon Horovitz, Jerome Eberhardt, Ivan Rivalta, Nikolay V. Dokholyan, Igor N. Berezovsky, Marco Cecchini, Le Yan, Hyunbum Jang, Dima Kozakov, Dzmitry Padhorny, VIB-VUB Center for Structural Biology [Bruxelles], VIB [Belgium], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut de Chimie de Strasbourg, Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Collège de France (CdF), Physics Department and INFN, University of Trento [Trento], Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS), Ecole Polytechnique Fédérale de Lausanne (EPFL), Laboratoire de Chimie - UMR5182 (LC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS ), Department of Biomedical Engineering [Boston], Boston University [Boston] (BU), University of Leeds, University of North Carolina at Chapel Hill, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), National University of Singapore (NUS), Weizmann Institute of Science [Rehovot, Israël], Johns Hopkins University (JHU), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Louis Pasteur - Strasbourg I-Institut de Chimie du CNRS (INC), Collège de France (CdF (institution)), Institute of Condensed Matter Physics [Lausanne], University of California [Santa Barbara] (UCSB), University of California, Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Institut de Chimie du CNRS (INC), Cancer and Inflammation Program, Leidos Biomedical Research Inc., Frederick National Laboratory, Frederick National Laboratory for Cancer Research (FNLCR), Stony Brook University [SUNY] (SBU), State University of New York (SUNY), University of York [York, UK], European Union's Horizon 2020 Research and Innovation Program under grant agreement no. 720270 (HBP SGA1)NIH grants R01GM114015, R01GM064803, and R01GM123247, grants P41GM103712 and P30DA035778Marie Curie Reintegration Grant (FP7-PEOPLE-2009-RG, no. 256533), European Project: 720270,H2020 Pilier Excellent Science,H2020-Adhoc-2014-20,HBP SGA1(2016), European Project: 256533,EC:FP7:PEOPLE,FP7-PEOPLE-2009-RG,COMPUT DRUG DESIGN(2010), Simulation of Biomolecular Systems (HIMS, FNWI), Wodak, Shoshana J, Paci, Emanuele, Dokholyan, Nikolay V, Berezovsky, Igor N, Horovitz, Amnon, Li, Jing, Hilser, Vincent J, Bahar, Ivet, Karanicolas, John, Stock, Gerhard, Hamm, Peter, Stote, Roland H, Eberhardt, Jerome, Chebaro, Yassmine, Dejaegere, Annick, Cecchini, Marco, Changeux, Jean-Pierre, Bolhuis, Peter G, Vreede, Jocelyne, Faccioli, Pietro, Orioli, Simone, Ravasio, Riccardo, Yan, Le, Brito, Carolina, Wyart, Matthieu, Gkeka, Paraskevi, Rivalta, Ivan, Palermo, Giulia, McCammon, J Andrew, Panecka-Hofman, Joanna, Wade, Rebecca C, Di Pizio, Antonella, Niv, Masha Y, Nussinov, Ruth, Tsai, Chung-Jung, Jang, Hyunbum, Padhorny, Dzmitry, Kozakov, Dima, McLeish, Tom, Wodak, S, Paci, E, Dokholyan, N, Berezovsky, I, Horovitz, A, Li, J, Hilser, V, Bahar, I, Karanicolas, J, Stock, G, Hamm, P, Stote, R, Eberhardt, J, Chebaro, Y, Dejaegere, A, Cecchini, M, Changeux, J, Bolhuis, P, Vreede, J, Faccioli, P, Orioli, S, Ravasio, R, Yan, L, Brito, C, Wyart, M, Gkeka, P, Rivalta, I, Palermo, G, Mccammon, J, Panecka-Hofman, J, Wade, R, Di Pizio, A, Niv, M, Nussinov, R, Tsai, C, Jang, H, Padhorny, D, Kozakov, D, Mcleish, T, and Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)
- Subjects
Transcription, Genetic ,Computer science ,nuclear receptors ,Biosensing Techniques ,allosteric switche ,Structural Biology ,chemical rescue ,Allostery ,ComputingMilieux_MISCELLANEOUS ,Cognitive science ,mechanisms ,0303 health sciences ,Protein function ,ligand-binding ,elastic network model ,molecular dynamic ,dynamic allostery ,030302 biochemistry & molecular biology ,regulation ,protein function ,Biological Sciences ,[SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,[CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry ,modulation ,Generic Health Relevance ,elastic network models ,Thermodynamics ,Transcription ,Allosteric Site ,Metabolic Networks and Pathways ,signal transduction ,Signal Transduction ,1.1 Normal biological development and functioning ,Biophysics ,allosteric drug ,Molecular Dynamics Simulation ,Article ,03 medical and health sciences ,protein conformational changes ,Genetic ,Allosteric Regulation ,Underpinning research ,conformational-changes ,Information and Computing Sciences ,Animals ,Humans ,Molecular Biology ,Elastic network models ,allosteric material ,030304 developmental biology ,pathway ,energy landscape ,Proteins ,allosteric switches ,molecular dynamics ,protein conformational change ,allosteric drugs ,Conceptual framework ,Gene Expression Regulation ,Drug Design ,network ,Chemical Sciences ,protein - Abstract
Allosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, and metabolism. Allostery is rooted in the fundamental physical properties of macromo-lecular systems, but its underlying mechanisms are still poorly understood. A collection of contributions to a recent interdisciplinary CECAM (Center Européen de Calcul Atomique et Moléculaire) workshop is used here to provide an overview of the progress and remaining limitations in the understanding of the mechanistic foundations of allostery gained from computational and experimental analyses of real protein systems and model systems. The main conceptual frameworks instrumental in driving the field are discussed. We illustrate the role of these frameworks in illuminating molecular mechanisms and explaining cellular processes, and describe some of their promising practical applications in engineering molecular sensors and informing drug design efforts.
- Published
- 2019
8. Substitutions at residue 211 in the prion protein drive a switch between CJD and GSS syndrome, a new mechanism governing inherited neurodegenerative disorders
- Author
-
Etienne Levavasseur, Jean-Louis Laplanche, Philippe Derreumaux, Human Rezaei, Céline Chapuis, Nicolas Privat, Katell Peoc'h, M. Borg, Isabelle Laffont-Proust, Pierre Bedoucha, Yassmine Chebaro, Annie Laquerrière, Stéphane Haïk, Jean-Jacques Hauw, Alfonso De Simone, Jean-Louis Kemeny, Jean-Philippe Brandel, Emilien Delmont, Service de Biochimie et de Biologie moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Faculté de Pharmacie-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Nice, Centre Hospitalier Universitaire de Nice (CHU Nice), Laboratoire de biochimie théorique [Paris] (LBT (UPR_9080)), Institut de biologie physico-chimique (IBPC (FR_550)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement (Néovasc), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-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), Service de Neurologie, Hôpital Pasteur [Nice] (CHU)-Centre Hospitalier Universitaire de Nice (CHU Nice), Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 'Institut National de la Sante et de la Recherche Medicale' (INSERM), 'Assistance Publique - Hopitaux de Paris (AP-HP), 'Fondation Thierry et Annick Desmarest - Institut de France', 'Institut National de Veille Sanitaire' (InVS, CNR-TNC), Hénin, Jérôme, 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 [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Neuropathologie Raymond Escourolle, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Peoc'H, K., Levavasseur, E., Delmont, E., De simone, A., Laffont-proust, I., Privat, N., Chebaro, Y., Chapuis, C., Bedoucha, P., Brandel, J., Laquerriere, A., Kemeny, J., Hauw, J., Borg, M., Rezaei, H., Derreumaux, P., Laplanche, J., Haik, S., Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Faculté de Pharmacie-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), 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], Centre National de la Recherche Scientifique (CNRS)-Institut de biologie physico-chimique (IBPC), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Service d'Anatomie et Cytologie Pathologique [Rouen], Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de recherche Virologie et Immunologie Moléculaires (VIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Faculté de Pharmacie-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], 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 ) -Centre National de la Recherche Scientifique ( CNRS ) -CHU Pitié-Salpêtrière [APHP], Laboratoire de biochimie théorique [Paris] ( LBT ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement ( Néovasc ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institute for Research and Innovation in Biomedicine ( IRIB ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Pasteur [Nice] ( CHU ) -CHU Nice, Unité de recherche Virologie et Immunologie Moléculaires ( VIM ), Institut National de la Recherche Agronomique ( INRA ), and CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC )
- Subjects
Models, Molecular ,[ SDV.BBM.BP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics ,Prions ,Protein Conformation ,animal diseases ,Mutant ,PrPSc Proteins ,[SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics ,Plaque, Amyloid ,Biology ,Molecular Dynamics Simulation ,medicine.disease_cause ,Creutzfeldt-Jakob Syndrome ,03 medical and health sciences ,0302 clinical medicine ,Protein structure ,Genetics ,medicine ,Gerstmann-Straussler-Scheinker Disease ,Humans ,Senile plaques ,Cloning, Molecular ,Phosphorylation ,Molecular Biology ,Gene ,Genetics (clinical) ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,Mutation ,General Medicine ,Phenotype ,3. Good health ,nervous system diseases ,[SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics ,Gliosis ,Amino Acid Substitution ,medicine.symptom ,030217 neurology & neurosurgery - Abstract
Human prion diseases are a heterogeneous group of fatal neurodegenerative disorders, characterized by the deposition of the partially protease-resistant prion protein (PrPres), astrocytosis, neuronal loss and spongiform change in the brain. Among inherited forms that represent 15% of patients, different phenotypes have been described depending on the variations detected at different positions within the prion protein gene. Here, we report a new mechanism governing the phenotypic variability of inherited prion diseases. First, we observed that the substitution at residue 211 with either Gln or Asp leads to distinct disorders at the clinical, neuropathological and biochemical levels (Creutzfeldt-Jakob disease or Gerstmann-Sträussler-Scheinker syndrome with abundant amyloid plaques and tau neurofibrillar pathology). Then, using molecular dynamics simulations and biophysical characterization of mutant proteins and an in vitro model of PrP conversion, we found evidence that each substitution impacts differently the stability of PrP and its propensity to produce different protease resistant fragments that may contribute to the phenotypical switch. Thus, subtle differences in the PrP primary structure and stability are sufficient to control amyloid plaques formation and tau abnormal phosphorylation and fibrillation. This mechanism is unique among neurodegenerative disorders and is consistent with the prion hypothesis that proposes a conformational change as the key pathological event in prion disorders. © The Author 2012. Published by Oxford University Press.
- Published
- 2012
9. A vitamin D-based strategy overcomes chemoresistance in prostate cancer.
- Author
-
Len-Tayon K, Beraud C, Fauveau C, Belorusova AY, Chebaro Y, Mouriño A, Massfelder T, Chauchereau A, Metzger D, Rochel N, and Laverny G
- Abstract
Background and Purpose: Castration-resistant prostate cancer (CRPC) is a common male malignancy that requires new therapeutic strategies due to acquired resistance to its first-line treatment, docetaxel. The benefits of vitamin D on prostate cancer (PCa) progression have been previously reported. This study aimed to investigate the effects of vitamin D on chemoresistance in CRPC., Experimental Approach: Structure function relationships of potent vitamin D analogues were determined. The combination of the most potent analogue and docetaxel was explored in chemoresistant primary PCa spheroids and in a xenograft mouse model derived from a patient with a chemoresistant CRPC., Key Results: Here, we show that Xe4MeCF3 is more potent than the natural ligand to induce vitamin D receptor (VDR) transcriptional activities and that it has a larger therapeutic window. Moreover, we demonstrate that VDR agonists restore docetaxel sensitivity in PCa spheroids. Importantly, Xe4MeCF3 reduces tumour growth in a chemoresistant CRPC patient-derived xenograft. In addition, this treatment targets signalling pathways associated with cancer progression in the remaining cells., Conclusion and Implications: Taken together, these results unravel the potency of VDR agonists to overcome chemoresistance in CRPC and open new avenues for the clinical management of PCa., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
- Published
- 2024
- Full Text
- View/download PDF
10. Vitamin D Analogs Bearing C-20 Modifications Stabilize the Agonistic Conformation of Non-Responsive Vitamin D Receptor Variants.
- Author
-
Belorusova AY, Rovito D, Chebaro Y, Doms S, Verlinden L, Verstuyf A, Metzger D, Rochel N, and Laverny G
- Subjects
- Humans, Ligands, Protein Binding, Vitamin D, Receptors, Calcitriol agonists, Rickets
- Abstract
The Vitamin D receptor (VDR) plays a key role in calcium homeostasis, as well as in cell proliferation and differentiation. Among the large number of VDR ligands that have been developed, we have previously shown that BXL-62 and Gemini-72, two C-20-modified vitamin D analogs are highly potent VDR agonists. In this study, we show that both VDR ligands restore the transcriptional activities of VDR variants unresponsive to the natural ligand and identified in patients with rickets. The elucidated mechanisms of action underlying the activities of these C-20-modified analogs emphasize the mutual adaptation of the ligand and the VDR ligand-binding pocket.
- Published
- 2022
- Full Text
- View/download PDF
11. High-Risk Mucosal Human Papillomavirus 16 (HPV16) E6 Protein and Cutaneous HPV5 and HPV8 E6 Proteins Employ Distinct Strategies To Interfere with Interferon Regulatory Factor 3-Mediated Beta Interferon Expression.
- Author
-
Poirson J, Suarez IP, Straub ML, Cousido-Siah A, Peixoto P, Hervouet E, Foster A, Mitschler A, Mukobo N, Chebaro Y, Garcin D, Recberlik S, Gaiddon C, Altschuh D, Nominé Y, Podjarny A, Trave G, and Masson M
- Subjects
- Human papillomavirus 16 metabolism, Humans, Mucous Membrane virology, Papillomaviridae metabolism, Skin virology, Interferon Regulatory Factor-3 genetics, Interferon Regulatory Factor-3 metabolism, Interferon-beta metabolism, Oncogene Proteins, Viral genetics, Oncogene Proteins, Viral metabolism, Papillomavirus Infections, Repressor Proteins genetics, Repressor Proteins metabolism
- Abstract
Persistent infection with some mucosal α-genus human papillomaviruses (HPVs; the most prevalent one being HPV16) can induce cervical carcinoma, anogenital cancers, and a subset of head and neck squamous cell carcinoma (HNSCC). Cutaneous β-genus HPVs (such as HPV5 and HPV8) associate with skin lesions that can progress into squamous cell carcinoma with sun exposure in Epidermodysplasia verruciformis patients and immunosuppressed patients. Here, we analyzed mechanisms used by E6 proteins from the α- and β-genus to inhibit the interferon-β (IFNB1) response. HPV16 E6 mediates this effect by a strong direct interaction with interferon regulatory factor 3 (IRF3). The binding site of E6 was localized within a flexible linker between the DNA-binding domain and the IRF-activation domain of IRF3 containing an LxxLL motif. The crystallographic structure of the complex between HPV16 E6 and the LxxLL motif of IRF3 was solved and compared with the structure of HPV16 E6 interacting with the LxxLL motif of the ubiquitin ligase E6AP. In contrast, cutaneous HPV5 and HPV8 E6 proteins bind to the IRF3-binding domain (IBiD) of the CREB-binding protein (CBP), a key transcriptional coactivator in IRF3-mediated IFN-β expression. IMPORTANCE Persistent HPV infections can be associated with the development of several cancers. The ability to persist depends on the ability of the virus to escape the host immune system. The type I interferon (IFN) system is the first-line antiviral defense strategy. HPVs carry early proteins that can block the activation of IFN-I. Among mucosal α-genus HPV types, the HPV16 E6 protein has a remarkable property to strongly interact with the transcription factor IRF3. Instead, cutaneous HPV5 and HPV8 E6 proteins bind to the IRF3 cofactor CBP. These results highlight the versatility of E6 proteins to interact with different cellular targets. The interaction between the HPV16 E6 protein and IRF3 might contribute to the higher prevalence of HPV16 than that of other high-risk mucosal HPV types in HPV-associated cancers.
- Published
- 2022
- Full Text
- View/download PDF
12. A structural signature motif enlightens the origin and diversification of nuclear receptors.
- Author
-
Beinsteiner B, Markov GV, Erb S, Chebaro Y, McEwen AG, Cianférani S, Laudet V, Moras D, and Billas IML
- Subjects
- Amino Acid Sequence genetics, Binding Sites genetics, Dimerization, Gene Expression Regulation, Developmental genetics, Gene Regulatory Networks genetics, Humans, Ligands, Promoter Regions, Genetic genetics, Receptors, Cytoplasmic and Nuclear chemistry, Receptors, Cytoplasmic and Nuclear genetics, Retinoid X Receptors ultrastructure, Transcription Factors chemistry, Transcription Factors genetics, Embryonic Development genetics, Receptors, Cytoplasmic and Nuclear ultrastructure, Retinoid X Receptors genetics, Transcription Factors ultrastructure
- Abstract
Nuclear receptors are ligand-activated transcription factors that modulate gene regulatory networks from embryonic development to adult physiology and thus represent major targets for clinical interventions in many diseases. Most nuclear receptors function either as homodimers or as heterodimers. The dimerization is crucial for gene regulation by nuclear receptors, by extending the repertoire of binding sites in the promoters or the enhancers of target genes via combinatorial interactions. Here, we focused our attention on an unusual structural variation of the α-helix, called π-turn that is present in helix H7 of the ligand-binding domain of RXR and HNF4. By tracing back the complex evolutionary history of the π-turn, we demonstrate that it was present ancestrally and then independently lost in several nuclear receptor lineages. Importantly, the evolutionary history of the π-turn motif is parallel to the evolutionary diversification of the nuclear receptor dimerization ability from ancestral homodimers to derived heterodimers. We then carried out structural and biophysical analyses, in particular through point mutation studies of key RXR signature residues and showed that this motif plays a critical role in the network of interactions stabilizing homodimers. We further showed that the π-turn was instrumental in allowing a flexible heterodimeric interface of RXR in order to accommodate multiple interfaces with numerous partners and critical for the emergence of high affinity receptors. Altogether, our work allows to identify a functional role for the π-turn in oligomerization of nuclear receptors and reveals how this motif is linked to the emergence of a critical biological function. We conclude that the π-turn can be viewed as a structural exaptation that has contributed to enlarging the functional repertoire of nuclear receptors., Competing Interests: The authors declare that they have no conflict of interest.
- Published
- 2021
- Full Text
- View/download PDF
13. BpForms and BcForms: a toolkit for concretely describing non-canonical polymers and complexes to facilitate global biochemical networks.
- Author
-
Lang PF, Chebaro Y, Zheng X, P Sekar JA, Shaikh B, Natale DA, and Karr JR
- Subjects
- Macromolecular Substances chemistry, Proteomics, Synthetic Biology, Systems Biology, Macromolecular Substances standards, Molecular Structure, Software
- Abstract
Non-canonical residues, caps, crosslinks, and nicks are important to many functions of DNAs, RNAs, proteins, and complexes. However, we do not fully understand how networks of such non-canonical macromolecules generate behavior. One barrier is our limited formats for describing macromolecules. To overcome this barrier, we develop BpForms and BcForms, a toolkit for representing the primary structure of macromolecules as combinations of residues, caps, crosslinks, and nicks. The toolkit can help omics researchers perform quality control and exchange information about macromolecules, help systems biologists assemble global models of cells that encompass processes such as post-translational modification, and help bioengineers design cells.
- Published
- 2020
- Full Text
- View/download PDF
14. Carboxylic Acid Transporters in Candida Pathogenesis.
- Author
-
Alves R, Sousa-Silva M, Vieira D, Soares P, Chebaro Y, Lorenz MC, Casal M, Soares-Silva I, and Paiva S
- Subjects
- Biological Transport, Candida genetics, Fungal Proteins metabolism, Gene Expression Regulation, Fungal, Humans, Membrane Transport Proteins metabolism, Phylogeny, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae metabolism, Candida chemistry, Candida pathogenicity, Carboxylic Acids metabolism, Fungal Proteins classification, Membrane Transport Proteins classification
- Abstract
Opportunistic pathogens such as Candida species can use carboxylic acids, like acetate and lactate, to survive and successfully thrive in different environmental niches. These nonfermentable substrates are frequently the major carbon sources present in certain human body sites, and their efficient uptake by regulated plasma membrane transporters plays a critical role in such nutrient-limited conditions. Here, we cover the physiology and regulation of these proteins and their potential role in Candida virulence. This review also presents an evolutionary analysis of orthologues of the Saccharomyces cerevisiae Jen1 lactate and Ady2 acetate transporters, including a phylogenetic analysis of 101 putative carboxylate transporters in twelve medically relevant Candida species. These proteins are assigned to distinct clades according to their amino acid sequence homology and represent the major carboxylic acid uptake systems in yeast. While Jen transporters belong to the sialate:H
+ symporter (SHS) family, the Ady2 homologue members are assigned to the acetate uptake transporter (AceTr) family. Here, we reclassify the later members as ATO (acetate transporter ortholog). The new nomenclature will facilitate the study of these transporters, as well as the analysis of their relevance for Candida pathogenesis., (Copyright © 2020 Alves et al.)- Published
- 2020
- Full Text
- View/download PDF
15. A multifunnel energy landscape encodes the competing α-helix and β-hairpin conformations for a designed peptide.
- Author
-
Chakraborty D, Chebaro Y, and Wales DJ
- Subjects
- Mutation, Peptides genetics, Protein Conformation, alpha-Helical genetics, Protein Conformation, beta-Strand genetics, Peptides chemistry
- Abstract
Depending on the amino acid sequence, as well as the local environment, some peptides have the capability to fold into multiple secondary structures. Conformational switching between such structures is a key element of protein folding and aggregation. Specifically, understanding the molecular mechanism underlying the transition from an α-helix to a β-hairpin is critical because it is thought to be a harbinger of amyloid assembly. In this study, we explore the energy landscape for an 18-residue peptide (DP5), designed by Araki and Tamura to exhibit equal propensities for the α-helical and β-hairpin forms. We find that the degeneracy is encoded in the multifunnel nature of the underlying free energy landscape. In agreement with experiment, we also observe that mutation of tyrosine at position 12 to serine shifts the equilibrium in favor of the α-helix conformation, by altering the landscape topography. The transition from the α-helix to the β-hairpin is a complex stepwise process, and occurs via collapsed coil-like intermediates. Our findings suggest that even a single mutation can tune the emergent features of the landscape, providing an efficient route to protein design. Interestingly, the transition pathways for the conformational switch seem to be minimally perturbed upon mutation, suggesting that there could be universal microscopic features that are conserved among different switch-competent protein sequences.
- Published
- 2020
- Full Text
- View/download PDF
16. Association Between Sarcopenic Obesity and Metabolic Syndrome in Adults: A Systematic Review and Meta-Analysis.
- Author
-
Khadra D, Itani L, Chebaro Y, Obeid M, Jaber M, Ghanem R, Ayton A, Kreidieh D, E Masri D, Kimura A, Tannir H, and El Ghoch M
- Subjects
- Aged, Female, Humans, Male, Metabolic Syndrome pathology, Obesity pathology, Prevalence, Risk Factors, Sarcopenia pathology, Metabolic Syndrome complications, Obesity complications, Sarcopenia complications
- Abstract
Background: In the last two decades, a new phenotype termed Sarcopenic Obesity (SO), in which sarcopenia and obesity coexist, has emerged., Objective: The aim of this systematic review and meta-analysis was first to assess the prevalence of Metabolic syndrome (Mets) among individuals with and without SO, and second, to determine if SO may increase the relative risk of Mets., Methods: This study was conducted in adherence to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines and the data were collated by means of metaanalysis and narrative synthesis., Results: Twelve studies including a total of 11,308 adults with overweight or obesity of both genders met the inclusion criteria and were reviewed, revealing two main findings. First, a similar overall prevalence of Mets in individuals with SO (61.49%; 95% CI: 52.19-70.40) when compared to those without SO (56.74%; 95% CI: 47.32-65.93) was identified. Second, the presence of SO appears not to increase the risk of Mets with respect to those without SO (RR = 1.08, 95% CI: 0.99- 1.17, p = 0.07)., Conclusion: No higher prevalence of Mets among individuals with SO when compared to those with obesity only, nor a significant association between SO and a higher risk of Mets was found., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2020
- Full Text
- View/download PDF
17. Structural Basis for DNA Gyrase Interaction with Coumermycin A1.
- Author
-
Vanden Broeck A, McEwen AG, Chebaro Y, Potier N, and Lamour V
- Subjects
- Adenosine Triphosphate chemistry, Adenosine Triphosphate metabolism, Aminocoumarins metabolism, Binding Sites, DNA Gyrase metabolism, Dimerization, Escherichia coli enzymology, Hydrogen Bonding, Molecular Dynamics Simulation, Protein Structure, Quaternary, Protein Subunits chemistry, Protein Subunits metabolism, Thermus thermophilus enzymology, Aminocoumarins chemistry, DNA Gyrase chemistry
- Abstract
Coumermycin A1 is a natural aminocoumarin that inhibits bacterial DNA gyrase, a member of the GHKL proteins superfamily. We report here the first cocrystal structures of gyrase B bound to coumermycin A1, revealing that one coumermycin A1 molecule traps simultaneously two ATP-binding sites. The inhibited dimers from different species adopt distinct sequence-dependent conformations, alternative to the ATP-bound form. These structures provide a basis for the rational development of coumermycin A1 derivatives for antibiotherapy and biotechnology applications.
- Published
- 2019
- Full Text
- View/download PDF
18. Allostery in Its Many Disguises: From Theory to Applications.
- Author
-
Wodak SJ, Paci E, Dokholyan NV, Berezovsky IN, Horovitz A, Li J, Hilser VJ, Bahar I, Karanicolas J, Stock G, Hamm P, Stote RH, Eberhardt J, Chebaro Y, Dejaegere A, Cecchini M, Changeux JP, Bolhuis PG, Vreede J, Faccioli P, Orioli S, Ravasio R, Yan L, Brito C, Wyart M, Gkeka P, Rivalta I, Palermo G, McCammon JA, Panecka-Hofman J, Wade RC, Di Pizio A, Niv MY, Nussinov R, Tsai CJ, Jang H, Padhorny D, Kozakov D, and McLeish T
- Subjects
- Allosteric Regulation, Animals, Gene Expression Regulation, Humans, Metabolic Networks and Pathways, Molecular Dynamics Simulation, Proteins genetics, Proteins metabolism, Signal Transduction, Thermodynamics, Transcription, Genetic, Allosteric Site, Biosensing Techniques, Drug Design, Proteins chemistry
- Abstract
Allosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, and metabolism. Allostery is rooted in the fundamental physical properties of macromolecular systems, but its underlying mechanisms are still poorly understood. A collection of contributions to a recent interdisciplinary CECAM (Center Européen de Calcul Atomique et Moléculaire) workshop is used here to provide an overview of the progress and remaining limitations in the understanding of the mechanistic foundations of allostery gained from computational and experimental analyses of real protein systems and model systems. The main conceptual frameworks instrumental in driving the field are discussed. We illustrate the role of these frameworks in illuminating molecular mechanisms and explaining cellular processes, and describe some of their promising practical applications in engineering molecular sensors and informing drug design efforts., (Copyright © 2019. Published by Elsevier Ltd.)
- Published
- 2019
- Full Text
- View/download PDF
19. Modulation of RXR-DNA complex assembly by DNA context.
- Author
-
Osz J, McEwen AG, Wolf J, Poussin-Courmontagne P, Peluso-Iltis C, Chebaro Y, Kieffer B, and Rochel N
- Subjects
- Animals, Binding Sites, Calorimetry, Crystallography, X-Ray, Humans, Magnetic Resonance Spectroscopy, Models, Molecular, Protein Binding, Protein Conformation, Protein Domains, DNA metabolism, Retinoid X Receptors chemistry, Retinoid X Receptors metabolism
- Abstract
Retinoid X Receptors (RXRs) act as dimer partners for several nuclear receptors including itself, binding to genomic DNA response elements and regulating gene transcription with cell and gene specificity. As homodimers, RXRs bind direct repeats of the half-site (A/G)G(G/T)TCA separated by 1 nucleotide (DR1) and little variability of this consensus site is observed for natural DR1s. However, these variations are responsible of the modulation of RXR receptors function through differential binding affinity and conformational changes. To further our understanding of the molecular mechanisms underlying RXR-DNA interactions, we examined how RXR DBDs bind to different DR1s using thermodynamics, X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy. We show that the half-site sequences modulate the binding cooperativity that results from the protein-protein contacts between the two DBDs. Chemical shifts perturbation NMR experiments revealed that sequence variations in half-sites induce changes that propagate from the protein-DNA interface to the dimerization interface throughout the DBD fold., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
20. NR3E receptors in cnidarians: A new family of steroid receptor relatives extends the possible mechanisms for ligand binding.
- Author
-
Khalturin K, Billas IML, Chebaro Y, Reitzel AM, Tarrant AM, Laudet V, and Markov GV
- Subjects
- Animals, Binding Sites genetics, Binding Sites physiology, Estrogen Receptor alpha genetics, Evolution, Molecular, Humans, Ligands, Molecular Docking Simulation, Hydra metabolism, Receptors, Steroid metabolism, Signal Transduction physiology
- Abstract
Steroid hormone receptors are important regulators of development and physiology in bilaterian animals, but the role of steroid signaling in cnidarians has been contentious. Cnidarians produce steroids, including A-ring aromatic steroids with a side-chain, but these are probably made through pathways different than the one used by vertebrates to make their A-ring aromatic steroids. Here we present comparative genomic analyses indicating the presence of a previously undescribed nuclear receptor family within medusozoan cnidarians, that we propose to call NR3E. This family predates the diversification of ERR/ER/SR in bilaterians, indicating that the first NR3 evolved in the common ancestor of the placozoan and cnidarian-bilaterian with lineage-specific loss in the anthozoans, even though multiple species in this lineage have been shown to produce aromatic steroids, whose function remain unclear. We discovered serendipitously that a cytoplasmic factor within epidermal cells of transgenic Hydra vulgaris can trigger the nuclear translocation of heterologously expressed human ERα. This led us to hypothesize that aromatic steroids may also be present in the medusozoan cnidarian lineage, which includes Hydra, and may explain the translocation of human ERα. Docking experiments with paraestrol A, a cnidarian A-ring aromatic steroid, into the ligand-binding pocket of Hydra NR3E indicates that, if an aromatic steroid is indeed the true ligand, which remains to be demonstrated, it would bind to the pocket through a partially distinct mechanism from the manner in which estradiol binds to vertebrate ER., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
21. Adaptation of Candida albicans to Reactive Sulfur Species.
- Author
-
Chebaro Y, Lorenz M, Fa A, Zheng R, and Gustin M
- Subjects
- Candida albicans genetics, Candida albicans pathogenicity, Gene Expression Regulation, Fungal, Mutation, Oxidative Stress drug effects, Promoter Regions, Genetic, Reactive Nitrogen Species metabolism, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae metabolism, Sulfites metabolism, Sulfites pharmacology, Sulfur metabolism, Sulfur pharmacology, Transcription Factors genetics, Adaptation, Physiological genetics, Anion Transport Proteins genetics, Candida albicans metabolism, Oxidative Stress genetics, Saccharomyces cerevisiae Proteins genetics
- Abstract
Candida albicans is an opportunistic fungal pathogen that is highly resistant to different oxidative stresses. How reactive sulfur species (RSS) such as sulfite regulate gene expression and the role of the transcription factor Zcf2 and the sulfite exporter Ssu1 in such responses are not known. Here, we show that C. albicans specifically adapts to sulfite stress and that Zcf2 is required for that response as well as induction of genes predicted to remove sulfite from cells and to increase the intracellular amount of a subset of nitrogen metabolites. Analysis of mutants in the sulfate assimilation pathway show that sulfite conversion to sulfide accounts for part of sulfite toxicity and that Zcf2-dependent expression of the SSU1 sulfite exporter is induced by both sulfite and sulfide. Mutations in the SSU1 promoter that selectively inhibit induction by the reactive nitrogen species (RNS) nitrite, a previously reported activator of SSU1 , support a model for C. albicans in which Cta4-dependent RNS induction and Zcf2-dependent RSS induction are mediated by parallel pathways, different from S. cerevisiae in which the transcription factor Fzf1 mediates responses to both RNS and RSS. Lastly, we found that endogenous sulfite production leads to an increase in resistance to exogenously added sulfite. These results demonstrate that C. albicans has a unique response to sulfite that differs from the general oxidative stress response, and that adaptation to internal and external sulfite is largely mediated by one transcription factor and one effector gene., (Copyright © 2017 by the Genetics Society of America.)
- Published
- 2017
- Full Text
- View/download PDF
22. Allosteric Regulation in the Ligand Binding Domain of Retinoic Acid Receptorγ.
- Author
-
Chebaro Y, Sirigu S, Amal I, Lutzing R, Stote RH, Rochette-Egly C, Rochel N, and Dejaegere A
- Subjects
- Humans, Ligands, Molecular Dynamics Simulation, Phosphorylation, Protein Binding, Retinoic Acid Receptor gamma, Allosteric Regulation physiology, Receptors, Retinoic Acid metabolism, Tretinoin metabolism
- Abstract
Retinoic acid (RA) plays key roles in cell differentiation and growth arrest through nuclear retinoic acid receptors (RARs), which are ligand-dependent transcription factors. While the main trigger of RAR activation is the binding of RA, phosphorylation of the receptors has also emerged as an important regulatory signal. Phosphorylation of the RARγ N-terminal domain (NTD) is known to play a functional role in neuronal differentiation. In this work, we investigated the phosphorylation of RARγ ligand binding domain (LBD), and present evidence that the phosphorylation status of the LBD affects the phosphorylation of the NTD region. We solved the X-ray structure of a phospho-mimetic mutant of the LBD (RARγ S371E), which we used in molecular dynamics simulations to characterize the consequences of the S371E mutation on the RARγ structural dynamics. Combined with simulations of the wild-type LBD, we show that the conformational equilibria of LBD salt bridges (notably R387-D340) are affected by the S371E mutation, which likely affects the recruitment of the kinase complex that phosphorylates the NTD. The molecular dynamics simulations also showed that a conservative mutation in this salt bridge (R387K) affects the dynamics of the LBD without inducing large conformational changes. Finally, cellular assays showed that the phosphorylation of the NTD of RARγ is differentially regulated by retinoic acid in RARγWT and in the S371N, S371E and R387K mutants. This multidisciplinary work highlights an allosteric coupling between phosphorylations of the LBD and the NTD of RARγ and supports the importance of structural dynamics involving electrostatic interactions in the regulation of RARs activity., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2017
- Full Text
- View/download PDF
23. Targeting the Two Oncogenic Functional Sites of the HPV E6 Oncoprotein with a High-Affinity Bivalent Ligand.
- Author
-
Ramirez J, Poirson J, Foltz C, Chebaro Y, Schrapp M, Meyer A, Bonetta A, Forster A, Jacob Y, Masson M, Deryckère F, and Travé G
- Subjects
- Adenoviridae genetics, Amino Acid Motifs, Binding Sites, Cell Death, Cell Line, DNA-Binding Proteins chemistry, Gene Expression, HeLa Cells, Human papillomavirus 16 chemistry, Human papillomavirus 18 chemistry, Humans, Ligands, Models, Molecular, Neoplasms metabolism, Neoplasms therapy, Oncogene Proteins, Viral chemistry, PDZ Domains, Papillomavirus Infections metabolism, Papillomavirus Infections therapy, Protein Binding, Recombinant Fusion Proteins chemistry, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins pharmacology, Repressor Proteins chemistry, Tumor Suppressor Protein p53 metabolism, DNA-Binding Proteins metabolism, Human papillomavirus 16 metabolism, Human papillomavirus 18 metabolism, Neoplasms virology, Oncogene Proteins, Viral metabolism, Papillomavirus Infections virology, Recombinant Fusion Proteins metabolism, Repressor Proteins metabolism
- Abstract
The E6 oncoproteins of high-risk mucosal (hrm) human papillomaviruses (HPVs) contain a pocket that captures LxxLL motifs and a C-terminal motif that recruits PDZ domains, with both functions being crucial for HPV-induced oncogenesis. A chimeric protein was built by fusing a PDZ domain and an LxxLL motif, both known to bind E6. NMR spectroscopy, calorimetry and a mammalian protein complementation assay converged to show that the resulting PDZ-LxxLL chimera is a bivalent nanomolar ligand of E6, while its separated PDZ and LxxLL components are only micromolar binders. The chimera binds to all of the hrm-HPV E6 proteins tested but not to low-risk mucosal or cutaneous HPV E6. Adenovirus-mediated expression of the chimera specifically induces the death of HPV-positive cells, concomitant with increased levels of the tumour suppressor P53, its transcriptional target p21, and the apoptosis marker cleaved caspase 3. The bifunctional PDZ-LxxLL chimera opens new perspectives for the diagnosis and treatment of HPV-induced cancers., (© 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.)
- Published
- 2015
- Full Text
- View/download PDF
24. Intrinsically disordered energy landscapes.
- Author
-
Chebaro Y, Ballard AJ, Chakraborty D, and Wales DJ
- Subjects
- Animals, Apoptosis Regulatory Proteins metabolism, Hydrogen Bonding, Mice, Molecular Dynamics Simulation, Protein Folding, Protein Structure, Secondary, Protein Structure, Tertiary, Solvents chemistry, Thermodynamics, Tumor Suppressor Proteins metabolism, Apoptosis Regulatory Proteins chemistry, Tumor Suppressor Proteins chemistry
- Abstract
Analysis of an intrinsically disordered protein (IDP) reveals an underlying multifunnel structure for the energy landscape. We suggest that such 'intrinsically disordered' landscapes, with a number of very different competing low-energy structures, are likely to characterise IDPs, and provide a useful way to address their properties. In particular, IDPs are present in many cellular protein interaction networks, and several questions arise regarding how they bind to partners. Are conformations resembling the bound structure selected for binding, or does further folding occur on binding the partner in a induced-fit fashion? We focus on the p53 upregulated modulator of apoptosis (PUMA) protein, which adopts an α-helical conformation when bound to its partner, and is involved in the activation of apoptosis. Recent experimental evidence shows that folding is not necessary for binding, and supports an induced-fit mechanism. Using a variety of computational approaches we deduce the molecular mechanism behind the instability of the PUMA peptide as a helix in isolation. We find significant barriers between partially folded states and the helix. Our results show that the favoured conformations are molten-globule like, stabilised by charged and hydrophobic contacts, with structures resembling the bound state relatively unpopulated in equilibrium.
- Published
- 2015
- Full Text
- View/download PDF
25. The OPEP protein model: from single molecules, amyloid formation, crowding and hydrodynamics to DNA/RNA systems.
- Author
-
Sterpone F, Melchionna S, Tuffery P, Pasquali S, Mousseau N, Cragnolini T, Chebaro Y, St-Pierre JF, Kalimeri M, Barducci A, Laurin Y, Tek A, Baaden M, Nguyen PH, and Derreumaux P
- Subjects
- Amyloid chemistry, DNA chemistry, Models, Molecular, Proteins chemistry, RNA chemistry
- Abstract
The OPEP coarse-grained protein model has been applied to a wide range of applications since its first release 15 years ago. The model, which combines energetic and structural accuracy and chemical specificity, allows the study of single protein properties, DNA-RNA complexes, amyloid fibril formation and protein suspensions in a crowded environment. Here we first review the current state of the model and the most exciting applications using advanced conformational sampling methods. We then present the current limitations and a perspective on the ongoing developments.
- Published
- 2014
- Full Text
- View/download PDF
26. Protein structural statistics with PSS.
- Author
-
Gaillard T, Schwarz BB, Chebaro Y, Stote RH, and Dejaegere A
- Subjects
- Cyclin-Dependent Kinase 2 chemistry, Cyclin-Dependent Kinase 2 metabolism, Humans, Models, Molecular, Protein Conformation, Proteins metabolism, Receptors, Cytoplasmic and Nuclear chemistry, Receptors, Cytoplasmic and Nuclear metabolism, Computational Biology methods, Proteins chemistry, Software
- Abstract
Characterizing the variability within an ensemble of protein structures is a common requirement in structural biology and bioinformatics. With the increasing number of protein structures becoming available, there is a need for new tools capable of automating the structural comparison of large ensemble of structures. We present Protein Structural Statistics (PSS), a command-line program written in Perl for Unix-like environments, dedicated to the calculation of structural statistics for a set of proteins. PSS can perform multiple sequence alignments, structure superpositions, calculate Cartesian and dihedral coordinate statistics, and execute cluster analyses. An HTML report that contains a convenient summary of results with figures, tables, and hyperlinks can also be produced. PSS is a new tool providing an automated way to compare multiple structures. It integrates various types of structural analyses through an user-friendly and flexible interface, facilitating the access to powerful but more specialized programs. PSS is easy to modify and extend and is distributed under a free and open source license. The relevance of PSS is illustrated by examples of application to pertinent biological problems.
- Published
- 2013
- Full Text
- View/download PDF
27. The asymmetric binding of PGC-1α to the ERRα and ERRγ nuclear receptor homodimers involves a similar recognition mechanism.
- Author
-
Takacs M, Petoukhov MV, Atkinson RA, Roblin P, Ogi FX, Demeler B, Potier N, Chebaro Y, Dejaegere A, Svergun DI, Moras D, and Billas IM
- Subjects
- Amino Acid Sequence, Humans, Models, Molecular, Molecular Sequence Data, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Protein Binding, Protein Conformation, Protein Folding, Protein Interaction Domains and Motifs, Protein Multimerization, Protein Subunits chemistry, Protein Subunits metabolism, Receptors, Estrogen chemistry, Scattering, Small Angle, Transcription Factors chemistry, X-Ray Diffraction, ERRalpha Estrogen-Related Receptor, Receptors, Estrogen metabolism, Transcription Factors metabolism
- Abstract
Background: PGC-1α is a crucial regulator of cellular metabolism and energy homeostasis that functionally acts together with the estrogen-related receptors (ERRα and ERRγ) in the regulation of mitochondrial and metabolic gene networks. Dimerization of the ERRs is a pre-requisite for interactions with PGC-1α and other coactivators, eventually leading to transactivation. It was suggested recently (Devarakonda et al) that PGC-1α binds in a strikingly different manner to ERRγ ligand-binding domains (LBDs) compared to its mode of binding to ERRα and other nuclear receptors (NRs), where it interacts directly with the two ERRγ homodimer subunits., Methods/principal Findings: Here, we show that PGC-1α receptor interacting domain (RID) binds in an almost identical manner to ERRα and ERRγ homodimers. Microscale thermophoresis demonstrated that the interactions between PGC-1α RID and ERR LBDs involve a single receptor subunit through high-affinity, ERR-specific L3 and low-affinity L2 interactions. NMR studies further defined the limits of PGC-1α RID that interacts with ERRs. Consistent with these findings, the solution structures of PGC-1α/ERRα LBDs and PGC-1α/ERRγ LBDs complexes share an identical architecture with an asymmetric binding of PGC-1α to homodimeric ERR., Conclusions/significance: These studies provide the molecular determinants for the specificity of interactions between PGC-1α and the ERRs, whereby negative cooperativity prevails in the binding of the coactivators to these receptors. Our work indicates that allosteric regulation may be a general mechanism controlling the binding of the coactivators to homodimers.
- Published
- 2013
- Full Text
- View/download PDF
28. Phosphorylation of the retinoic acid receptor alpha induces a mechanical allosteric regulation and changes in internal dynamics.
- Author
-
Chebaro Y, Amal I, Rochel N, Rochette-Egly C, Stote RH, and Dejaegere A
- Subjects
- Allosteric Regulation, Allosteric Site, Animals, Binding Sites, Cell Nucleus metabolism, Computer Simulation, Crystallography, X-Ray, Cyclin H chemistry, Ligands, Mice, Phosphorylation, Protein Binding, Protein Structure, Secondary, Retinoic Acid Receptor alpha, Salts chemistry, Serine chemistry, Signal Transduction, Solvents chemistry, Transcriptional Activation, Tretinoin metabolism, Gene Expression Regulation, Receptors, Retinoic Acid metabolism
- Abstract
Nuclear receptor proteins constitute a superfamily of proteins that function as ligand dependent transcription factors. They are implicated in the transcriptional cascades underlying many physiological phenomena, such as embryogenesis, cell growth and differentiation, and apoptosis, making them one of the major signal transduction paradigms in metazoans. Regulation of these receptors occurs through the binding of hormones, and in the case of the retinoic acid receptor (RAR), through the binding of retinoic acid (RA). In addition to this canonical scenario of RAR activity, recent discoveries have shown that RAR regulation also occurs as a result of phosphorylation. In fact, RA induces non-genomic effects, such as the activation of kinase signaling pathways, resulting in the phosphorylation of several targets including RARs themselves. In the case of RARα, phosphorylation of Ser369 located in loop L9-10 of the ligand-binding domain leads to an increase in the affinity for the protein cyclin H, which is part of the Cdk-activating kinase complex of the general transcription factor TFIIH. The cyclin H binding site in RARα is situated more than 40 Å from the phosphorylated serine. Using molecular dynamics simulations of the unphosphorylated and phosphorylated forms of the receptor RARα, we analyzed the structural implications of receptor phosphorylation, which led to the identification of a structural mechanism for the allosteric coupling between the two remote sites of interest. The results show that phosphorylation leads to a reorganization of a local salt bridge network, which induces changes in helix extension and orientation that affects the cyclin H binding site. This results in changes in conformation and flexibility of the latter. The high conservation of the residues implicated in this signal transduction suggests a mechanism that could be applied to other nuclear receptor proteins.
- Published
- 2013
- Full Text
- View/download PDF
29. Substitutions at residue 211 in the prion protein drive a switch between CJD and GSS syndrome, a new mechanism governing inherited neurodegenerative disorders.
- Author
-
Peoc'h K, Levavasseur E, Delmont E, De Simone A, Laffont-Proust I, Privat N, Chebaro Y, Chapuis C, Bedoucha P, Brandel JP, Laquerriere A, Kemeny JL, Hauw JJ, Borg M, Rezaei H, Derreumaux P, Laplanche JL, and Haïk S
- Subjects
- Amino Acid Substitution, Cloning, Molecular, Creutzfeldt-Jakob Syndrome pathology, Gerstmann-Straussler-Scheinker Disease pathology, Humans, Models, Molecular, Molecular Dynamics Simulation, Mutation, Phenotype, Phosphorylation, Plaque, Amyloid genetics, Plaque, Amyloid metabolism, Prions metabolism, Protein Conformation, Creutzfeldt-Jakob Syndrome genetics, Gerstmann-Straussler-Scheinker Disease genetics, Prions genetics
- Abstract
Human prion diseases are a heterogeneous group of fatal neurodegenerative disorders, characterized by the deposition of the partially protease-resistant prion protein (PrP(res)), astrocytosis, neuronal loss and spongiform change in the brain. Among inherited forms that represent 15% of patients, different phenotypes have been described depending on the variations detected at different positions within the prion protein gene. Here, we report a new mechanism governing the phenotypic variability of inherited prion diseases. First, we observed that the substitution at residue 211 with either Gln or Asp leads to distinct disorders at the clinical, neuropathological and biochemical levels (Creutzfeldt-Jakob disease or Gerstmann-Sträussler-Scheinker syndrome with abundant amyloid plaques and tau neurofibrillar pathology). Then, using molecular dynamics simulations and biophysical characterization of mutant proteins and an in vitro model of PrP conversion, we found evidence that each substitution impacts differently the stability of PrP and its propensity to produce different protease resistant fragments that may contribute to the phenotypical switch. Thus, subtle differences in the PrP primary structure and stability are sufficient to control amyloid plaques formation and tau abnormal phosphorylation and fibrillation. This mechanism is unique among neurodegenerative disorders and is consistent with the prion hypothesis that proposes a conformational change as the key pathological event in prion disorders.
- Published
- 2012
- Full Text
- View/download PDF
30. Structural basis for the accommodation of bis- and tris-aromatic derivatives in vitamin D nuclear receptor.
- Author
-
Ciesielski F, Sato Y, Chebaro Y, Moras D, Dejaegere A, and Rochel N
- Subjects
- Animals, Benzene Derivatives pharmacology, Biphenyl Compounds chemistry, Biphenyl Compounds pharmacology, Calcitriol chemistry, Crystallography, X-Ray, HeLa Cells, Humans, Ligands, Phenyl Ethers chemistry, Phenyl Ethers pharmacology, Protein Structure, Secondary, Protein Structure, Tertiary, Receptors, Calcitriol agonists, Receptors, Calcitriol genetics, Static Electricity, Structure-Activity Relationship, Transcriptional Activation, Zebrafish Proteins agonists, Zebrafish Proteins chemistry, Zebrafish Proteins genetics, Benzene Derivatives chemistry, Models, Molecular, Receptors, Calcitriol chemistry
- Abstract
Actual use of the active form of vitamin D (calcitriol or 1α,25-dihydroxyvitamin D(3)) to treat hyperproliferative disorders is hampered by calcemic effects, hence the continuous development of chemically modified analogues with dissociated profiles. Structurally distinct nonsecosteroidal analogues have been developed to mimic calcitriol activity profiles with low calcium serum levels. Here, we report the crystallographic study of vitamin D nuclear receptor (VDR) ligand binding domain in complexes with six nonsecosteroidal analogues harboring two or three phenyl rings. These compounds induce a stimulated transcription in the nanomolar range, similar to calcitriol. Examination of the protein-ligand interactions reveals the mode of binding of these nonsecosteroidal compounds and highlights the role of the various chemical modifications of the ligands to VDR binding and activity, notably (de)solvation effects. The structures with the tris-aromatic ligands exhibit a rearrangement of a novel region of the VDR ligand binding pocket, helix H6.
- Published
- 2012
- Full Text
- View/download PDF
31. The coarse-grained OPEP force field for non-amyloid and amyloid proteins.
- Author
-
Chebaro Y, Pasquali S, and Derreumaux P
- Subjects
- Amyloidogenic Proteins metabolism, Hydrogen Bonding, Magnetic Resonance Spectroscopy, Molecular Dynamics Simulation, Prions chemistry, Protein Folding, Protein Structure, Secondary, Temperature, Thermodynamics, Amyloidogenic Proteins chemistry
- Abstract
Coarse-grained protein models with various levels of granularity and degrees of freedom offer the possibility to explore many phenomena including folding, assembly, and recognition in terms of dynamics and thermodynamics that are inaccessible to all-atom representations in explicit aqueous solution. Here, we present a refined version of the coarse-grained optimized potential for efficient protein structure prediction (OPEP) based on a six-bead representation. The OPEP version 4.0 parameter set, which uses a new analytical formulation for the nonbonded interactions and adds specific side-chain-side-chain interactions for α-helix, is subjected to three tests. First, we show that molecular dynamics simulations at 300 K preserve the experimental rigid conformations of 17 proteins with 37-152 amino acids within a root-mean-square deviation (RMSD) of 3.1 Å after 30 ns. Extending the simulation time to 100 ns for five proteins does not change the RMSDs. Second, replica exchange molecular dynamics (REMD) simulations recover the NMR structures of three prototypical β-hairpin and α-helix peptides and the NMR three-stranded β-sheet topology of a 37-residue WW domain, starting from randomly chosen states. Third, REMD simulations on the ccβ peptide show a temperature transition from a three-stranded coiled coil to amyloid-like aggregates consistent with experiments, while simulations on low molecular weight aggregates of the prion protein helix 1 do not. Overall, these studies indicate the effectiveness of our OPEP4 coarse-grained model for protein folding and aggregation, and report two future directions for improvement.
- Published
- 2012
- Full Text
- View/download PDF
32. Structures of Aβ17-42 trimers in isolation and with five small-molecule drugs using a hierarchical computational procedure.
- Author
-
Chebaro Y, Jiang P, Zang T, Mu Y, Nguyen PH, Mousseau N, and Derreumaux P
- Subjects
- Alzheimer Disease metabolism, Amino Acid Sequence, Amyloid beta-Peptides metabolism, Humans, Molecular Sequence Data, Peptide Fragments metabolism, Protein Conformation drug effects, Small Molecule Libraries chemistry, Alzheimer Disease drug therapy, Amyloid beta-Peptides antagonists & inhibitors, Amyloid beta-Peptides chemistry, Molecular Docking Simulation, Peptide Fragments antagonists & inhibitors, Peptide Fragments chemistry, Protein Multimerization drug effects, Small Molecule Libraries pharmacology
- Abstract
The amyloid-β protein (Aβ) oligomers are believed to be the main culprits in the cytoxicity of Alzheimer's disease (AD) and p3 peptides (Aβ17-42 fragments) are present in AD amyloid plaques. Many small-molecule or peptide-based inhibitors are known to slow down Aβ aggregation and reduce the toxicity in vitro, but their exact modes of action remain to be determined since there has been no atomic level of Aβ(p3)-drug oligomers. In this study, we have determined the structure of Aβ17-42 trimers both in aqueous solution and in the presence of five small-molecule inhibitors using a multiscale computational study. These inhibitors include 2002-H20, curcumin, EGCG, Nqtrp, and resveratrol. First, we used replica exchange molecular dynamics simulations coupled to the coarse-grained (CG) OPEP force field. These CG simulations reveal that the conformational ensemble of Aβ17-42 trimer can be described by 14 clusters with each peptide essentially adopting turn/random coil configurations, although the most populated cluster is characterized by one peptide with a β-hairpin at Phe19-Leu31. Second, these 14 dominant clusters and the less-frequent fibril-like state with parallel register of the peptides were subjected to atomistic Autodock simulations. Our analysis reveals that the drugs have multiple binding modes with different binding affinities for trimeric Aβ17-42 although they interact preferentially with the CHC region (residues 17-21). The compounds 2002-H20 and Nqtrp are found to be the worst and best binders, respectively, suggesting that the drugs may interfere at different stages of Aβ oligomerization. Finally, explicit solvent molecular dynamics of two predicted Nqtrp-Aβ17-42 conformations describe at atomic level some possible modes of action for Nqtrp.
- Published
- 2012
- Full Text
- View/download PDF
33. Structures and thermodynamics of Alzheimer's amyloid-beta Abeta(16-35) monomer and dimer by replica exchange molecular dynamics simulations: implication for full-length Abeta fibrillation.
- Author
-
Chebaro Y, Mousseau N, and Derreumaux P
- Subjects
- Amyloid chemistry, Amyloid beta-Peptides, Computer Simulation, Peptide Fragments, Protein Conformation, Thermodynamics, Alzheimer Disease, Models, Molecular, Protein Multimerization
- Abstract
Many proteins display a strand-loop-strand motif in their amyloid fibrillar states. For instance, the amyloid beta-protein, Abeta1-40, associated with Alzheimer's disease, displays a loop at positions 22-28 in its amyloid fibril state. It has been suggested that this loop could appear early in the aggregation process, but quantitative information regarding its presence in small oligomers remains scant. Because residues 1-15 are disordered in Abeta1-42 fibrils and Abeta10-35 forms fibrils in vitro, we select the peptide Abeta16-35, centered on residues 22-28 and determine the structures and thermodynamics of the monomer and dimer using coarse-grained implicit solvent replica exchange molecular dynamics simulations. Our simulations totalling 5 mus for the monomer and 12 micros for the dimer show no sign of strong secondary structure signals in both instances and the significant impact of dimerization on the global structure of Abeta16-35. They reveal however that the loop 22-28 acts as a quasi-independent unit in both species. The loop structure ensemble we report in Abeta16-35 monomer and dimer has high similarity to the loop formed by the Abeta21-30 peptide in solution and, to a lesser extent, to the loop found in Abeta1-40 fibrils. We discuss the implications of our findings on the assembly of full-length Abeta.
- Published
- 2009
- Full Text
- View/download PDF
34. The conversion of helix H2 to beta-sheet is accelerated in the monomer and dimer of the prion protein upon T183A mutation.
- Author
-
Chebaro Y and Derreumaux P
- Subjects
- Models, Molecular, Protein Denaturation, Protein Structure, Quaternary, Protein Structure, Secondary, Transition Temperature, Point Mutation, Prions chemistry, Prions genetics, Protein Multimerization
- Abstract
The conversion of the prion protein (PrP) from its cellular form, PrPC, to its pathogenic scrapie form, PrPSc, is a key event in neurodegenerative transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease (CJD). PrPC is characterized by three helices (H1-H3) and a small antiparallel beta-sheet. One working hypothesis for TSE causation is that oligomeric forms of PrP are the proximate neurotoxic agents. Because these states are transient in character, current experimental studies have failed to provide atomic structures. To gain insights into these intermediates, we have studied PrP125-228 and its CJD-causing T183A variant in their monomer and dimer forms by means of coarse-grained protein molecular dynamics simulations. Our 1.5 microsecond simulations show that the decrease in the thermodynamic stability of PrP monomer upon T183A, consistent with experimental studies, results from a destabilization of the H2H3 subdomain. Comparison of the monomer and dimer properties from wild-type and T183A PrP reveals that helix H1 is robust and the H2H3 subdomain displays a much higher propensity for intra- and inter-beta-sheets in T183A than in the wild-type sequence under denaturing conditions. However, both species display negligible beta-sheet structure. Implications of our simulations on prion propagation are discussed.
- Published
- 2009
- Full Text
- View/download PDF
35. Targeting the early steps of Abeta16-22 protofibril disassembly by N-methylated inhibitors: a numerical study.
- Author
-
Chebaro Y and Derreumaux P
- Subjects
- Amyloid chemistry, Computer Simulation, Humans, Methylation, Models, Molecular, Protein Binding, Protein Conformation, Protein Structure, Secondary, Alzheimer Disease metabolism, Amyloid metabolism, Amyloid beta-Peptides chemistry, Amyloid beta-Peptides metabolism, Peptide Fragments chemistry, Peptide Fragments metabolism
- Abstract
Aggregation of the Abeta1-40/Abeta1-42 peptides is a key factor in Alzheimer's disease. Though the inhibitory effect of N-methylated Abeta16-22 (mAbeta16-22) peptides is well characterized in vitro, there is little information on how they disassemble full-length Abeta fibrils or block fibril formation. Here, we report coarse-grained implicit solvent molecular dynamics (MD) and replica exchange molecular dynamics (REMD) simulations on Abeta16-22 and mAbeta16-22 monomers, and then a preformed six-chain Abeta16-22 bilayer with either four copies of Abeta16-22 or four copies of mAbeta16-22. Our simulations show that the effect of N-methylation on mAbeta16-22 monomer is to reduce the density of compact forms. While 100 ns MD trajectories do not reveal any significant differences between the two ten-chain systems, the REMD simulations totaling 1 micros help understand the first steps of Abeta16-22 protofibril disassembly by N-methylated inhibitors. Notably, we find that mAbeta16-22 preferentially interacts with Abeta16-22 by blocking both beta-sheet extension and lateral association of layers, but also by intercalation of the inhibitors allowing sequestration of Abeta16-22 peptides. This third binding mode is particularly appealing for blocking Abeta fibrillogenesis.
- Published
- 2009
- Full Text
- View/download PDF
36. Replica exchange molecular dynamics simulations of coarse-grained proteins in implicit solvent.
- Author
-
Chebaro Y, Dong X, Laghaei R, Derreumaux P, and Mousseau N
- Subjects
- Amino Acid Sequence, Computer Simulation, Magnetic Resonance Spectroscopy, Molecular Sequence Data, Peptides chemistry, Protein Folding, Proteins chemistry, Solvents chemistry, Temperature, Thermodynamics, Protein Structure, Secondary
- Abstract
Current approaches aimed at determining the free energy surface of all-atom medium-size proteins in explicit solvent are slow and are not sufficient to converge to equilibrium properties. To ensure a proper sampling of the configurational space, it is preferable to use reduced representations such as implicit solvent and/or coarse-grained protein models, which are much lighter computationally. Each model must be verified, however, to ensure that it can recover experimental structures and thermodynamics. Here we test the coarse-grained implicit solvent OPEP model with replica exchange molecular dynamics (REMD) on six peptides ranging in length from 10 to 28 residues: two alanine-based peptides, the second beta-hairpin from protein G, the Trp-cage and zinc-finger motif, and a dimer of a coiled coil peptide. We show that REMD-OPEP recovers the proper thermodynamics of the systems studied, with accurate structural description of the beta-hairpin and Trp-cage peptides (within 1-2 A from experiments). The light computational burden of REMD-OPEP, which enables us to generate many hundred nanoseconds at each temperature and fully assess convergence to equilibrium ensemble, opens the door to the determination of the free energy surface of larger proteins and assemblies.
- Published
- 2009
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.