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Mechanism of microtubule stabilization by taccalonolide AJ
As a major component of the cytoskeleton, microtubules consist of αβ-tubulin heterodimers and have been recognized as attractive targets for cancer chemotherapy. Microtubule-stabilizing agents (MSAs) promote polymerization of tubulin and stabilize the polymer, preventing depolymerization. The molecu...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467209/ https://www.ncbi.nlm.nih.gov/pubmed/28585532 http://dx.doi.org/10.1038/ncomms15787 |
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author | Wang, Yuxi Yu, Yamei Li, Guo-Bo Li, Shu-Ang Wu, Chengyong Gigant, Benoît Qin, Wenming Chen, Hao Wu, Yangping Chen, Qiang Yang, Jinliang |
author_facet | Wang, Yuxi Yu, Yamei Li, Guo-Bo Li, Shu-Ang Wu, Chengyong Gigant, Benoît Qin, Wenming Chen, Hao Wu, Yangping Chen, Qiang Yang, Jinliang |
author_sort | Wang, Yuxi |
collection | PubMed |
description | As a major component of the cytoskeleton, microtubules consist of αβ-tubulin heterodimers and have been recognized as attractive targets for cancer chemotherapy. Microtubule-stabilizing agents (MSAs) promote polymerization of tubulin and stabilize the polymer, preventing depolymerization. The molecular mechanisms by which MSAs stabilize microtubules remain elusive. Here we report a 2.05 Å crystal structure of tubulin complexed with taccalonolide AJ, a newly identified taxane-site MSA. Taccalonolide AJ covalently binds to β-tubulin D226. On AJ binding, the M-loop undergoes a conformational shift to facilitate tubulin polymerization. In this tubulin–AJ complex, the E-site of tubulin is occupied by GTP rather than GDP. Biochemical analyses confirm that AJ inhibits the hydrolysis of the E-site GTP. Thus, we propose that the β-tubulin E-site is locked into a GTP-preferred status by AJ binding. Our results provide experimental evidence for the connection between MSA binding and tubulin nucleotide state, and will help design new MSAs to overcome taxane resistance. |
format | Online Article Text |
id | pubmed-5467209 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-54672092017-06-19 Mechanism of microtubule stabilization by taccalonolide AJ Wang, Yuxi Yu, Yamei Li, Guo-Bo Li, Shu-Ang Wu, Chengyong Gigant, Benoît Qin, Wenming Chen, Hao Wu, Yangping Chen, Qiang Yang, Jinliang Nat Commun Article As a major component of the cytoskeleton, microtubules consist of αβ-tubulin heterodimers and have been recognized as attractive targets for cancer chemotherapy. Microtubule-stabilizing agents (MSAs) promote polymerization of tubulin and stabilize the polymer, preventing depolymerization. The molecular mechanisms by which MSAs stabilize microtubules remain elusive. Here we report a 2.05 Å crystal structure of tubulin complexed with taccalonolide AJ, a newly identified taxane-site MSA. Taccalonolide AJ covalently binds to β-tubulin D226. On AJ binding, the M-loop undergoes a conformational shift to facilitate tubulin polymerization. In this tubulin–AJ complex, the E-site of tubulin is occupied by GTP rather than GDP. Biochemical analyses confirm that AJ inhibits the hydrolysis of the E-site GTP. Thus, we propose that the β-tubulin E-site is locked into a GTP-preferred status by AJ binding. Our results provide experimental evidence for the connection between MSA binding and tubulin nucleotide state, and will help design new MSAs to overcome taxane resistance. Nature Publishing Group 2017-06-06 /pmc/articles/PMC5467209/ /pubmed/28585532 http://dx.doi.org/10.1038/ncomms15787 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Wang, Yuxi Yu, Yamei Li, Guo-Bo Li, Shu-Ang Wu, Chengyong Gigant, Benoît Qin, Wenming Chen, Hao Wu, Yangping Chen, Qiang Yang, Jinliang Mechanism of microtubule stabilization by taccalonolide AJ |
title | Mechanism of microtubule stabilization by taccalonolide AJ |
title_full | Mechanism of microtubule stabilization by taccalonolide AJ |
title_fullStr | Mechanism of microtubule stabilization by taccalonolide AJ |
title_full_unstemmed | Mechanism of microtubule stabilization by taccalonolide AJ |
title_short | Mechanism of microtubule stabilization by taccalonolide AJ |
title_sort | mechanism of microtubule stabilization by taccalonolide aj |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467209/ https://www.ncbi.nlm.nih.gov/pubmed/28585532 http://dx.doi.org/10.1038/ncomms15787 |
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