Cevipabulin-tubulin complex reveals a novel agent binding site on α-tubulin with tubulin degradation effect
Jianhong Yang, Yamei Yu, Yong Li, Wei Yan, Haoyu Ye, Lu Niu, Minghai Tang, Zhoufeng Wang, Zhuang Yang, Heying Pei, Haoche Wei, Min Zhao, Jiaolin Wen, Linyu Yang, Liang Ouyang, Yuquan Wei, Qiang Chen, Weimin Li, Lijuan Chen
Abstract
Microtubules, composed of αβ-tubulin heterodimers, have remained popular anticancer targets for decades. Six known binding sites on tubulin dimers have been identified thus far, with five sites on β-tubulin and only one site on α-tubulin, hinting that compounds binding to α-tubulin are less well characterized. Cevipabulin, a microtubule-active antitumor clinical candidate, is widely accepted as a microtubule-stabilizing agent by binding to the vinblastine site. Our x-ray crystallography study reveals that, in addition to binding to the vinblastine site, cevipabulin also binds to a new site on α-tubulin. We find that cevipabulin at this site pushes the αT5 loop outward, making the nonexchangeable GTP exchangeable, which reduces the stability of tubulin, leading to its destabilization and degradation. Our results confirm the existence of a new agent binding site on α-tubulin and shed light on the development of tubulin degraders as a new generation of antimicrotubule drugs targeting this novel site.