Cevipabulin-tubulin complex reveals a novel agent binding site on α-tubulin with tubulin degradation effect

43Citations
Citations of this article
33Readers
Mendeley users who have this article in their library.

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.

Cite

CITATION STYLE

APA

Yang, J., Yu, Y., Li, Y., Yan, W., Ye, H., Niu, L., … Chen, L. (2021). Cevipabulin-tubulin complex reveals a novel agent binding site on α-tubulin with tubulin degradation effect. Science Advances, 7(21). https://doi.org/10.1126/sciadv.abg4168

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free