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The Structure of MT189-Tubulin Complex Provides Insights into Drug Design

文献类型：期刊论文

作者Li, Zhongping1,2; Ma, Lingling1,2; Wu, Chengyong1,2; Meng, Tao3; Ma, Lanping3; Zheng, Wenyue4; Yu, Yamei1,2; Chen, Qiang1,2; Yang, Jinliang1,2; Shen, Jingkang3
刊名LETTERS IN DRUG DESIGN & DISCOVERY
出版日期2019
卷号16期号:9页码:1069-1073
关键词Crystal structure tubulin colchicine binding site inhibitor MT189 drug design
ISSN号1570-1808
DOI10.2174/1570180816666181122122655
通讯作者Yu, Yamei(yamei_yu@scu.edu.cn) ; Chen, Qiang(qiang_chen@scu.edu.cn)
英文摘要Background: Drugs that interfere with microtubule dynamics are used widely in cancer chemotherapy. Microtubules are composed of alpha beta-tubulin heterodimers, and the colchicine binding site of tubulin is an important pocket for designing tubulin polymerization inhibitors. We have previously designed and synthesized a series of colchicine binding site inhibitors (CBSIs). However, these compounds showed no anticancer activity in vivo. Then, we have used a deconstruction approach to obtain a new derivative MT189, which showed in vivo anticancer activity. Methods: We crystallized a protein complex including two tubulins, one stathmin-like domain of RB3 and one tubulin tyrosine ligase, and soaked MT189 into the crystals. We collected the diffraction data and determined the tubulin-MT189 structure to 2.8 angstrom. Results: Here, we report the crystal structure of tubulin complexed with MT189, elucidate how the small-molecular agent binds to tubulin and inhibits microtubule assembly, and explain previous results of the structure-activity-relationship studies. Conclusion: The tubulin-MT189 complex structure reveals the interactions between this agent and tubulin and provides insights into the design of new derivatives targeting the colchicine binding site.
WOS关键词COLCHICINE ; MODEL ; SITE
资助项目National Natural Science Foundation of China[81672722] ; National Natural Science Foundation of China[81501368] ; National Natural Science Foundation of China[81473130] ; National Natural Science Foundation of China[81473092] ; National Natural Science Foundation of China[31741027] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2014ZX09508001]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000485622300009
出版者BENTHAM SCIENCE PUBL LTD
源URL[http://119.78.100.183/handle/2S10ELR8/288667]  
专题新药研究国家重点实验室
通讯作者Yu, Yamei; Chen, Qiang
作者单位1.Sichuan Univ, West China Hosp, Canc Ctr, Chengdu 610041, Sichuan, Peoples R China
2.Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Sichuan, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Div Med Chem, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Sichuan Univ, West China Hosp Stomatol, Dept Cariol & Endodont, State Key Lab Oral Dis,Natl Clin Res Ctr Oral Dis, Chengdu 610041, Sichuan, Peoples R China
推荐引用方式
GB/T 7714		 Li, Zhongping,Ma, Lingling,Wu, Chengyong,et al. The Structure of MT189-Tubulin Complex Provides Insights into Drug Design[J]. LETTERS IN DRUG DESIGN & DISCOVERY,2019,16(9):1069-1073.
APA Li, Zhongping.,Ma, Lingling.,Wu, Chengyong.,Meng, Tao.,Ma, Lanping.,...&Shen, Jingkang.(2019).The Structure of MT189-Tubulin Complex Provides Insights into Drug Design.LETTERS IN DRUG DESIGN & DISCOVERY,16(9),1069-1073.
MLA Li, Zhongping,et al."The Structure of MT189-Tubulin Complex Provides Insights into Drug Design".LETTERS IN DRUG DESIGN & DISCOVERY 16.9(2019):1069-1073.

入库方式： OAI收割

来源：上海药物研究所

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