دورية أكاديمية
Structural insight into the stabilization of microtubules by taxanes
| العنوان: | Structural insight into the stabilization of microtubules by taxanes |
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| المؤلفون: | Prota, Andrea E., Lucena-Agell, Daniel, Ma, Yuntao, Estévez-Gallego, Juan, Li, Shuo, Bargsten, Katja, Josa-Prado, Fernando, Altmann, Karl-Heinz, Gaillard, Natacha, Kamimura, Shinji, Mühlethaler, Tobias, Gago, Federico, Oliva, María A., Steinmetz, Michel O., Fang, Wei-Shuo, Díaz, José Fernando |
| المساهمون: | 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., Díaz, José Fernando |
| بيانات النشر: | eLife Sciences Publications |
| سنة النشر: | 2023 |
| المجموعة: | Digital.CSIC (Consejo Superior de Investigaciones Científicas / Spanish National Research Council) |
| الوصف: | 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 ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 2050-084X |
| العلاقة: | #PLACEHOLDER_PARENT_METADATA_VALUE#; info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104545RB-I00/ES/BASES ESTRUCTURALES DE LA NEUROTOXICIDAD POR ANTITUMORALES DIRIGIDOS CONTRA TUBULINA: HACIA MEJORES MODULADORES DE MICROTUBULOS CONTRA CANCER Y ENFERMEDADES NEURODEGENERATIVAS/; info:eu-repo/grantAgreement/EC/H2020/860070; info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104070RB-C22/ES/ESTUDIOS BIOQUIMICOS Y DE MODELADO MOLECULAR PARA EL DISEÑO, CRIBADO Y CARACTERIZACION DE ENTIDADES QUIMICAS INNOVADORAS FRENTE A LEISHMANIASIS E INFECCIONES POR RNA-VIRUS/; Publisher's version; https://doi.org/10.7554/eLife.84791Test; Sí; eLife 12: e84791 (2023); http://hdl.handle.net/10261/306117Test |
| DOI: | 10.7554/eLife.84791 |
| الإتاحة: | https://doi.org/10.7554/eLife.84791Test http://hdl.handle.net/10261/306117Test |
| حقوق: | open |
| رقم الانضمام: | edsbas.F63A5F79 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 2050084X |
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| DOI: | 10.7554/eLife.84791 |