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

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Author(s): Zhongping Li, Lingling Ma, Chengyong Wu, Tao Meng, Lanping Ma, Wenyue Zheng, Yamei Yu*, Qiang Chen*, Jinliang Yang, Jingkang Shen.

Journal Name: Letters in Drug Design & Discovery

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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.

Keywords: Crystal structure, tubulin, colchicine binding site, inhibitor, MT189, drug design.

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(E-pub Ahead of Print)
DOI: 10.2174/1570180816666181122122655
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