机构：[1]State Key Laboratory of Biotherapy and Cancer Center,West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.四川大学华西医院[2]Department of Respiratory Medicine, West China Hospital of Sichuan University, Chengdu 610041, China.四川大学华西医院[3]Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Universite′ Paris-Saclay, Gif-sur-Yvette 91198, France.[4]National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 201210, China.
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.
基金：
National Major Scientific and Technological Special Project for ‘Significant New Drugs
Development’ (2012ZX09103301-030), National Natural Science Foundation of China (81372822, 81501368 and 81672722) and the Fondation ARC pour la Recherche
sur le Cancer.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2017]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
最新[2023]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
第一作者：
第一作者机构：[1]State Key Laboratory of Biotherapy and Cancer Center,West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.[2]Department of Respiratory Medicine, West China Hospital of Sichuan University, Chengdu 610041, China.
通讯作者：
推荐引用方式(GB/T 7714)：
Wang Yuxi,Yu Yamei,Li Guo-Bo,et al.Mechanism of microtubule stabilization by taccalonolide AJ.[J].Nature communications.2017,8:15787.doi:10.1038/ncomms15787.
APA：
Wang Yuxi,Yu Yamei,Li Guo-Bo,Li Shu-Ang,Wu Chengyong...&Yang Jinliang.(2017).Mechanism of microtubule stabilization by taccalonolide AJ..Nature communications,8,
MLA：
Wang Yuxi,et al."Mechanism of microtubule stabilization by taccalonolide AJ.".Nature communications 8.(2017):15787
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