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Structures of a diverse set of colchicine binding site inhibitors in complex with tubulin provide a rationale for drug discovery.

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资源类型：
Pubmed体系：
作者：
Wang Yuxi[1] * ; Zhang Hang[1] * ; Gigant Benoît[2] ; Yu Yamei[1] ; Wu Yangping[1] ; Chen Xiangzheng[1] ; Lai Qinhuai[1] ; Yang Zhaoya[3] ; Chen Qiang[1,*1] ; Yang Jinliang[1,*1] ;
机构： [1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China. [2]Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Gif-sur-Yvette, France. [3]West China School of Pharmacy, Sichuan University, Chengdu, China.
出处：
DOI： 10.1111/febs.13555
ISSN：

关键词： colchicine binding domain crystal structure drug design pharmacophore tubulin inhibitor

摘要：
Microtubules are dynamic assemblies of αβ-tubulin heterodimers and have been recognized as highly attractive targets for cancer chemotherapy. A broad range of agents bind to tubulin and interfere with microtubule assembly. Despite having a long history of characterization, colchicine binding site inhibitors (CBSIs) have not yet reached the commercial phase as anti-cancer drugs to date. We determined the structures of tubulin complexed with a set of structurally diverse CBSIs (lexibulin, nocodazole, plinabulin and tivantinib), among which nocodazole and tivantinib are both binary-function inhibitors targeting cancer-related kinases and microtubules simultaneously. High resolution structures revealed the detailed interactions between these ligands and tubulin. Our results showed that the binding modes of the CBSIs were different from previous docking models, highlighting the importance of crystal structure information in structure-based drug design. A real structure-based pharmacophore was proposed to rationalize key common interactions of the CBSIs at the colchicine domain. Our studies provide a solid structural basis for developing new anti-cancer agents for the colchicine binding site. The atomic coordinates and structure factors for tubulin complexed with lexibulin, nocodazole, plinabulin and tivantinib have been deposited in the Protein Data Bank under accession codes 5CA0, 5CA1, 5C8Y and 5CB4, respectively. © 2015 FEBS.

基金：
This work was supported by research funding received from National Major Scientific and Technological Special Project for ‘Significant New Drugs Development’ (2012ZX09103301-030), National Natu ral Science Foundation of China (81372822) and Scientific Research Foundation for the Returned Overseas Chinese Scholars (2014-1685-11-9), State Education Ministry.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2016]版：
大类 | 2 区 生物
小类 | 3 区 生化与分子生物学
最新[2023]版：
大类 | 2 区 生物学
小类 | 3 区 生化与分子生物学
第一作者：
第一作者机构： [1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China.
共同第一作者：
通讯作者：
通讯机构： [1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China. [*1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
推荐引用方式(GB/T 7714)：
Wang Yuxi,Zhang Hang,Gigant Benoît,et al.Structures of a diverse set of colchicine binding site inhibitors in complex with tubulin provide a rationale for drug discovery.[J].The FEBS journal.2016,283(1):102-11.doi:10.1111/febs.13555.
APA：
Wang Yuxi,Zhang Hang,Gigant Benoît,Yu Yamei,Wu Yangping...&Yang Jinliang.(2016).Structures of a diverse set of colchicine binding site inhibitors in complex with tubulin provide a rationale for drug discovery..The FEBS journal,283,(1)
MLA：
Wang Yuxi,et al."Structures of a diverse set of colchicine binding site inhibitors in complex with tubulin provide a rationale for drug discovery.".The FEBS journal 283..1(2016):102-11

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