Title:The Structure of MT189-Tubulin Complex Provides Insights into Drug Design
VOLUME: 16 ISSUE: 9
Author(s):Zhongping Li, Lingling Ma, Chengyong Wu, Tao Meng, Lanping Ma, Wenyue Zheng, Yamei Yu*, Qiang Chen*, Jinliang Yang and Jingkang Shen
Affiliation:Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, Division of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, Division of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, Division of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203
Keywords:Crystal structure, tubulin, colchicine binding site, inhibitor, MT189, drug design.
Abstract:
Background: Drugs that interfere with microtubule dynamics are used widely in cancer
chemotherapy. Microtubules are composed of αβ-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 Å.
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.
