7CLD

Crystal structure of T2R-TTL-Cevipabulin complex

Summary for 7CLD

• Entry DOI: 10.2210/pdb7cld/pdb
• Descriptor: Tubulin alpha-1B chain, 6-[2,6-bis(fluoranyl)-4-[3-(methylamino)propoxy]phenyl]-5-chloranyl-N-[(2S)-1,1,1-tris(fluoranyl)propan-2-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (12 entities in total)
• Functional Keywords: tubulin inhibitor, tublin, structural protein
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 6
• Total formula weight: 265349.88

Authors

Chen, L.J.,Chen, Q.,Yu, Y.,Yang, J.H. (deposition date: 2020-07-20, release date: 2021-07-07, Last modification date: 2023-11-29)

Primary citation

Yang, J.,Yu, Y.,Li, Y.,Yan, W.,Ye, H.,Niu, L.,Tang, M.,Wang, Z.,Yang, Z.,Pei, H.,Wei, H.,Zhao, M.,Wen, J.,Yang, L.,Ouyang, L.,Wei, Y.,Chen, Q.,Li, W.,Chen, L.
Cevipabulin-tubulin complex reveals a novel agent binding site on alpha-tubulin with tubulin degradation effect.
Sci Adv, 7:-, 2021

PubMed 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.

PubMed: 34138737
DOI: 10.1126/sciadv.abg4168

Experimental method

X-RAY DIFFRACTION (2.611 Å)