14 results on '"Gaillard, Natacha"'
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2. Inhibiting parasite proliferation using a rationally designed anti‐tubulin agent
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Gaillard, Natacha, Sharma, Ashwani, Abbaali, Izra, Liu, Tianyang, Shilliday, Fiona, Cook, Alexander D, Ehrhard, Valentin, Bangera, Mamata, Roberts, Anthony J, Moores, Carolyn A, Morrissette, Naomi, and Steinmetz, Michel O
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Biochemistry and Cell Biology ,Biological Sciences ,Emerging Infectious Diseases ,Infectious Diseases ,Biodefense ,2.2 Factors relating to the physical environment ,5.1 Pharmaceuticals ,Infection ,Good Health and Well Being ,Animals ,Antiparasitic Agents ,Binding Sites ,Cell Proliferation ,Humans ,Microtubules ,Parasites ,Tubulin ,Tubulin Modulators ,anti-parasite ,microtubules ,rational structure-based drug design ,species-specific tubulin inhibitor ,Medical and Health Sciences ,Biochemistry and cell biology - Abstract
Infectious diseases caused by apicomplexan parasites remain a global public health threat. The presence of multiple ligand-binding sites in tubulin makes this protein an attractive target for anti-parasite drug discovery. However, despite remarkable successes as anti-cancer agents, the rational development of protozoan parasite-specific tubulin drugs has been hindered by a lack of structural and biochemical information on protozoan tubulins. Here, we present atomic structures for a protozoan tubulin and microtubule and delineate the architectures of apicomplexan tubulin drug-binding sites. Based on this information, we rationally designed the parasite-specific tubulin inhibitor parabulin and show that it inhibits growth of parasites while displaying no effects on human cells. Our work presents for the first time the rational design of a species-specific tubulin drug providing a framework to exploit structural differences between human and protozoa tubulin variants enabling the development of much-needed, novel parasite inhibitors.
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- 2021
3. 3-nitropyridine analogues as novel microtubule-targeting agents.
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Herman, Jean, Vanstreels, Els, Bardiot, Dorothée, Prota, Andrea E., Gaillard, Natacha, Gao, Ling-Jie, Vercruysse, Thomas, Persoons, Leentje, Daems, Tinne, Waer, Mark, Herdewijn, Piet, Louat, Thierry, Steinmetz, Michel O., De Jonghe, Steven, Sprangers, Ben, and Daelemans, Dirk
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COLON cancer ,X-ray crystallography ,ANTINEOPLASTIC agents ,CELL cycle ,TUMOR growth ,TUBULINS - Abstract
Microtubule-targeting agents are an important class of anti-cancer drugs; their full potential is however not realized because of significant myelotoxicity and neurotoxicity. We here report 3-nitropyridine analogues as a novel group of microtubule-targeting agents with potent anti-cancer effects against a broad range of cancer types. We show that these 3-nitropyridines induce cell cycle arrest in the G2-M phase and inhibit tubulin polymerization by interacting with tubulin. Determination of the tubulin–4AZA2996 structure by X-ray crystallography demonstrated that this class of compounds binds to the colchicine-site of tubulin. Furthermore, the anti-cancer effect was demonstrated both in vitro and in vivo in a murine heterotopic xenograft model of colon cancer. When administered intravenously, 4AZA2891 effectively inhibited cancer growth. Whereas 3-nitropyridine compounds do not induce myelotoxicity at pharmacological doses, the neurotoxicity associated with microtubule-targeting agents is still present. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Direct observation of coherent azobenzene photochemistry
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Standfuss, Jörg, primary, Weinert, Tobias, additional, Wranik, Maximillian, additional, Church, Jonathan, additional, Seidel, Hans Peter, additional, Slavov, Chavdar, additional, Masini, Tiziana, additional, James, Daniel, additional, Glover, Hannah, additional, Carrillo, Melissa, additional, Kekilli, Demet, additional, Stipp, Robin, additional, Skopintsev, Petr, additional, Bruenle, Steffen, additional, Gaillard, Natacha, additional, Furrer, Antonia, additional, Gashi, Dardan, additional, Mühlethaler, Tobias, additional, Beale, John, additional, Nass, Karol, additional, Johnson, Philip, additional, Cirelli, Claudio, additional, Ozerov, Dmitry, additional, Dworkowski, Florian, additional, Bacellar, Camila, additional, Milne, Christopher, additional, Steinmetz, Michel, additional, Wachtveitl, Josef, additional, and Schapiro, Igor, additional
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- 2023
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5. Structural insight into the stabilization of microtubules by taxanes
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Prota, Andrea E, primary, Lucena-Agell, Daniel, additional, Ma, Yuntao, additional, Estevez-Gallego, Juan, additional, Li, Shuo, additional, Bargsten, Katja, additional, Josa-Prado, Fernando, additional, Altmann, Karl-Heinz, additional, Gaillard, Natacha, additional, Kamimura, Shinji, additional, Mühlethaler, Tobias, additional, Gago, Federico, additional, Oliva, Maria A, additional, Steinmetz, Michel O, additional, Fang, Wei-Shuo, additional, and Díaz, J Fernando, additional
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- 2023
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6. Changes in seam number and location induce holes within microtubules assembled from porcine brain tubulin and in Xenopus egg cytoplasmic extracts
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Guyomar, Charlotte, primary, Bousquet, Clément, additional, Ku, Siou, additional, Heumann, John M, additional, Guilloux, Gabriel, additional, Gaillard, Natacha, additional, Heichette, Claire, additional, Duchesne, Laurence, additional, Steinmetz, Michel O, additional, Gibeaux, Romain, additional, and Chrétien, Denis, additional
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- 2022
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7. Author response: Changes in seam number and location induce holes within microtubules assembled from porcine brain tubulin and in Xenopus egg cytoplasmic extracts
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Guyomar, Charlotte, primary, Bousquet, Clément, additional, Ku, Siou, additional, Heumann, John M, additional, Guilloux, Gabriel, additional, Gaillard, Natacha, additional, Heichette, Claire, additional, Duchesne, Laurence, additional, Steinmetz, Michel O, additional, Gibeaux, Romain, additional, and Chrétien, Denis, additional
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- 2022
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8. Release of a photopharmacological drug from its protein target captured by time-resolved serial crystallography
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Wranik, Maximilian, primary, Weinert, Tobias, additional, Slavov, Chavdar, additional, Masini, Tiziana, additional, Furrer, Antonia, additional, Gaillard, Natacha, additional, Gioia, Dario, additional, Ferrarotti, Marco, additional, James, Daniel, additional, Glover, Hannah, additional, Carrillo, Melissa, additional, Kekilli, Demet, additional, Stipp, Robin, additional, Skopintsev, Petr, additional, Brünle, Steffen, additional, Mühlethaler, Tobias, additional, Beale, John, additional, Gashi, Dardan, additional, Nass, Karol, additional, Ozerov, Dmitry, additional, Johnson, Philip, additional, Cirelli, Claudio, additional, Bacellar, Camila, additional, Braun, Markus, additional, Wang, Meitian, additional, Dworkowski, Florian, additional, Milne, Christopher, additional, Cavalli, Andrea, additional, Wachtveitl, Josef, additional, Steinmetz, Michel, additional, and Standfuss, Jörg, additional
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- 2022
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9. Molecular snapshots of drug release from tubulin over eleven orders of magnitude in time
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Wranik, Maximillian, primary, Weinert, Tobias, additional, Slavov, Chavdar, additional, Masini, Tiziana, additional, Furrer, Antonia, additional, Gaillard, Natacha, additional, Gioia, Dario, additional, Ferrarotti, Marco, additional, James, Daniel, additional, Glover, Hannah, additional, Carrillo, Melissa, additional, Kekilli, Demet, additional, Stipp, Robin, additional, Skopintsev, Petr, additional, Brünle, Steffen, additional, Mühlethaler, Tobias, additional, Beale, John, additional, Gashi, Dardan, additional, Nass, Karol, additional, Ozerov, Dmitry, additional, Johnson, Philip J.M., additional, Cirelli, Claudio, additional, Bacellar, Camila, additional, Braun, Markus, additional, Wang, Meitian, additional, Dworkowski, Florian, additional, Milne, Chris, additional, Cavalli, Andrea, additional, Wachtveitl, Josef, additional, Steinmetz, Michel O., additional, and Standfuss, Jörg, additional
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- 2022
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10. Structural heterogeneity of the microtubule lattice
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Métivier, Mathieu, Gallaud, Emmanuel, Thomas, Alexandre, Pascal, Aude, Gagné, Jean-Philippe, Poirier, Guy, Chrétien, Denis, Gibeaux, Romain, Richard-Parpaillon, Laurent, Benaud, Christelle, Giet, Régis, Guyomar, Charlotte, Ku, Siou, Heumann, John, Bousquet, Clément, Guilloux, Gabriel, Gaillard, Natacha, Heichette, Claire, Duchesne, Laurence, Steinmetz, Michel, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Laval [Québec] (ULaval), University of Colorado [Boulder], and Paul Scherrer Institute (PSI)
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[SDV]Life Sciences [q-bio] - Abstract
Microtubules are polymers assembled from αβ-tubulin heterodimers. They typically display lateral α-α and β-β homotypic interactions, except at one region, called the seam, where heterotypic α-β and β-α interactions occur. Here, we decorated microtubules assembled in vitro or in cytoplasmic Xenopus egg extracts with kinesin-motor domains, and analyzed their lattice organization using dual axis cryo-electron tomography followed by segmented sub-tomogram averaging. In both conditions, microtubules incorporated variable protofilament and/or tubulin subunit helix start numbers. While microtubules assembled in vitro displayed variable numbers of seams, those assembled in extracts displayed preferentially one seam. The seam location varied within individual microtubules implying the presence of lattice holes. Thus, the formation of discontinuous microtubule lattices is an intrinsic property of tubulin assembly, a process that is controlled in cells. One-Sentence Summary Microtubules assembled from purified tubulin form discontinuous lattices, an intrinsic property strictly controlled in cytoplasmic Xenopus egg extracts.
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- 2021
11. Structural heterogeneity of the microtubule lattice
- Author
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Guyomar, Charlotte, Ku, Siou, Heumann, John, Bousquet, Clément, Guilloux, Gabriel, Gaillard, Natacha, Heichette, Claire, Duchesne, Laurence, Steinmetz, Michel, Gibeaux, Romain, Chrétien, Denis, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University of Colorado [Boulder], Paul Scherrer Institute (PSI), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
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[SDV]Life Sciences [q-bio] - Abstract
Microtubules are polymers assembled from αβ-tubulin heterodimers. They typically display lateral α-α and β-β homotypic interactions, except at one region, called the seam, where heterotypic α-β and β-α interactions occur. Here, we decorated microtubules assembled in vitro or in cytoplasmic Xenopus egg extracts with kinesin-motor domains, and analyzed their lattice organization using dual axis cryo-electron tomography followed by segmented sub-tomogram averaging. In both conditions, microtubules incorporated variable protofilament and/or tubulin subunit helix start numbers. While microtubules assembled in vitro displayed variable numbers of seams, those assembled in extracts displayed preferentially one seam. The seam location varied within individual microtubules implying the presence of lattice holes. Thus, the formation of discontinuous microtubule lattices is an intrinsic property of tubulin assembly, a process that is controlled in cells. One-Sentence Summary Microtubules assembled from purified tubulin form discontinuous lattices, an intrinsic property strictly controlled in cytoplasmic Xenopus egg extracts.
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- 2021
12. Structural insight into the stabilization of microtubules by taxanes
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Prota, Andrea E., primary, Lucena-Agell, Daniel, additional, Ma, Yuntao, additional, Estévez-Gallego, Juan, additional, Li, Shuo, additional, Bargsten, Katja, additional, Josa-Prado, Fernando, additional, Altmann, Karl-Heinz, additional, Gaillard, Natacha, additional, Kamimura, Shinji, additional, Mühlethaler, Tobias, additional, Gago, Federico, additional, Oliva, María A., additional, Steinmetz, Michel O., additional, Fang, Wei-Shuo, additional, and Díaz, J. Fernando, additional
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- 2021
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13. Changes in seam number and location induce holes within microtubules assembled from porcine brain tubulin and in Xenopus egg cytoplasmic extracts
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Guyomar, Charlotte, primary, Bousquet, Clément, additional, Ku, Siou, additional, Heumann, John, additional, Guilloux, Gabriel, additional, Gaillard, Natacha, additional, Heichette, Claire, additional, Duchesne, Laurence, additional, Steinmetz, Michel O., additional, Gibeaux, Romain, additional, and Chrétien, Denis, additional
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- 2021
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14. Structural insight into the stabilization of microtubules by taxanes
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Andrea E Prota, Daniel Lucena-Agell, Yuntao Ma, Juan Estevez-Gallego, Shuo Li, Katja Bargsten, Fernando Josa-Prado, Karl-Heinz Altmann, Natacha Gaillard, Shinji Kamimura, Tobias Mühlethaler, Federico Gago, Maria A Oliva, Michel O Steinmetz, Wei-Shuo Fang, J Fernando Díaz, Ministerio de Ciencia e Innovación (España), Consejo Superior de Investigaciones Científicas (España), Fundación Tatiana Pérez de Guzmán el Bueno, European Commission, Swiss National Science Foundation, Japan Society for the Promotion of Science, National Natural Science Foundation of China, Chinese Academy of Medical Sciences, Prota, Andrea E., Lucena-Agell, Daniel, Estévez-Gallego, Juan, Josa-Prado, Fernando, Altmann, Karl-Heinz, Gaillard, Natacha, Kamimura, Shinji, Mühlethaler, Tobias, Gago, Federico, Oliva, María A., Steinmetz, Michel O., and Díaz, José Fernando
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General Immunology and Microbiology ,General Neuroscience ,General Medicine ,General Biochemistry, Genetics and Molecular Biology - Abstract
35 p.-12 fig.-2 tab.-3 animat.-1 schem.This article is dedicated to the memory of Dr Linda Amos, a dear friend and pioneer in the study of microtubules and the mechanism of action of paclitaxel (Amos and Löwe, 1999), who passed away while we were assembling this manuscript., Paclitaxel (Taxol) is a taxane and a chemotherapeutic drug that stabilizes microtubules. While the interaction of paclitaxel with microtubules is well described, the lack of high-resolution structural information on a tubulin-taxane complex precludes a comprehensive description of the binding determinants that affect its mechanism of action. Here, we solved the crystal structure of baccatin III the core moiety of paclitaxel-tubulin complex at 1.9 Å resolution. Based on this information, we engineered taxanes with modified C13 side chains, solved their crystal structures in complex with tubulin, and analyzed their effects on microtubules (X-ray fiber diffraction), along with those of paclitaxel, docetaxel, and baccatin III. Further comparison of high-resolution structures and microtubules’ diffractions with the apo forms and molecular dynamics approaches allowed us to understand the consequences of taxane binding to tubulin in solution and under assembled conditions. The results sheds light on three main mechanistic questions: (1) taxanes bind better to microtubules than to tubulin because tubulin assembly is linked to a βM-loopconformational reorganization (otherwise occludes the access to the taxane site) and, bulky C13 side chains preferentially recognize the assembled conformational state; (2) the occupancy of the taxane site has no influence on the straightness of tubulin protofilaments and; (3) longitudinal expansion of the microtubule lattices arises from the accommodation of the taxane core within the site, a process that is no related to the microtubule stabilization (baccatin III is biochemically inactive). In conclusion, our combined experimental and computational approach allowed us to describe the tubulin-taxane interaction in atomic detail and assess the structural determinants for binding., Ministerio de Ciencia e Innovación (PID2019-104545RB-I00 (AEI/10.13039/501100011033)) J Fernando Díaz Consejo Superior de Investigaciones Científicas (PIE 201920E111) J Fernando Díaz Fundación Tatiana Pérez de Guzmán el Bueno (Proyecto de Investigación en Neurociencia 2020) J Fernando Díaz European Union NextGenerationEU (H2020-MSCA-ITN-2019 860070 TUBINTRAIN) Andrea E Prota J Fernando Díaz Swiss National Science Foundation (310030_192566) Michel O Steinmetz JSPS KAKENHI (16K07328/17H03668) Shinji Kamimura National Natural Science Foundation of China (30930108) Wei-Shuo Fang Chinese Academy of Medical Sciences (2016-I2M-1-010) Wei-Shuo Fang Ministerio de Ciencia e Innovación (PID2019-104070RB-C22 (AEI/10.13039/501100011033)) Federico Gago We thank Ganadería Fernando Díaz for calf brains supply and staff of beamlines X06DA of the Swiss Light Source (Paul Scherrer Institut, Villigen PSI, Switzerland) and BL11-NDC-SWEET (ALBA, Cerdanyola del Vallès, Spain) for their support. We also thank Mr Pedro Gascón Blanco for his private donation to the project to support a month of a student salary.
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- 2023
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