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

doi:10.2174/1570180816666181122122655

	The Structure of MT189-Tubulin Complex Provides Insights into Drug Design
	Li, Zhongping 1,2; Ma, Lingling 1,2; Wu, Chengyong 1,2; Meng, Tao 3; Ma, Lanping 3; Zheng, Wenyue 4; Yu, Yamei 1,2; Chen, Qiang 1,2; Yang, Jinliang 1,2; Shen, Jingkang 3
刊名	LETTERS IN DRUG DESIGN & DISCOVERY
	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
DOI	10.2174/1570180816666181122122655
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.
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关键词	COLCHICINE ; MODEL ; SITE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	BENTHAM SCIENCE PUBL LTD
WOS记录号	WOS:000485622300009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/288667]
专题	中国科学院上海药物研究所
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.