机构：[1]Cancer Center, West China Hospital, Sichuan University, Chengdu, China四川大学华西医院[2]Department of Clinical Research, West China Hospital, Sichuan University, Chengdu, China四川大学华西医院[3]Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China四川大学华西医院[4]Precision Medicine Research Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China四川大学华西医院[5]State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China[6]Chinese Academy of Sciences, Shanghai Synchrotron Radiation Facility Science Center, Shanghai Advanced Research Institute, China
Tubulin vinca-domain ligands can inhibit microtubule polymerization, causing cell death in mitosis, and their potential against multiple cancer types has been demonstrated. However, due to drug resistance and toxicities, development of novel vinca-domain ligands is still needed. In this study, we determined the high-resolution crystal structures of vinorelbine, YXD and Phomopsin A in complex with tubulin at 2.5 Å. Additionally, we recapitulated all previously published high-resolution crystal structures of the vinca binding site to reveal critical residues and the molecular mechanism of vinca-domain ligands interacting with tubulin. Furthermore, we designed putatively novel triazolopyrimidine derivatives by introducing secondary amine groups to establish salt-bridge and H-bond interactions with Asp179β1 and Asn329α2 . Our studies provided the structural basis for designing novel tubulin vinca-domain ligands.
This article is protected by copyright. All rights reserved.
基金：
This work was supported by National Natural
Science Foundation of China (81703553), Sichuan
Science and Technology Program (2019YFS0003), China
Postdoctoral Science Foundation (2018T110984,
2017M610607), NationalMajor Scientific and Technological
Special Project for ‘Significant New Drugs Development’
(2018ZX09201018-021), Post-Doctor Research
Project, West China Hospital, Sichuan University
(2018HXBH057).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2021]版：
大类|3 区生物学
小类|3 区生物物理4 区生化与分子生物学4 区细胞生物学
最新[2023]版：
大类|4 区生物学
小类|4 区生化与分子生物学4 区生物物理4 区细胞生物学
第一作者：
第一作者机构：[1]Cancer Center, West China Hospital, Sichuan University, Chengdu, China
共同第一作者：
通讯作者：
通讯机构：[1]Cancer Center, West China Hospital, Sichuan University, Chengdu, China[6]Chinese Academy of Sciences, Shanghai Synchrotron Radiation Facility Science Center, Shanghai Advanced Research Institute, China[*1]Chinese Academy of Sciences, Shanghai Synchrotron Radiation Facility Science Center, No. 239 Zhangheng Rd., Shanghai Advanced Research Institute, Shanghai 201204, China[*2]Cancer Center, West China Hospital, Sichuan University, No. 17 South Renmin Rd., Chengdu, Sichuan 201204, China
推荐引用方式(GB/T 7714)：
Wu Chengyong,Xian Jinghong,Wang Yanyan,et al.The high-resolution X-ray structure of vinca domain inhibitors of microtubules provides a rational approach for drug design.[J].FEBS letters.2021,595(2):195-205.doi:10.1002/1873-3468.14003.
APA：
Wu Chengyong,Xian Jinghong,Wang Yanyan,Xiao Qing-Jie,Ma Lingling...&Wang Yuxi.(2021).The high-resolution X-ray structure of vinca domain inhibitors of microtubules provides a rational approach for drug design..FEBS letters,595,(2)
MLA：
Wu Chengyong,et al."The high-resolution X-ray structure of vinca domain inhibitors of microtubules provides a rational approach for drug design.".FEBS letters 595..2(2021):195-205
