7cld
Crystal structure of T2R-TTL-Cevipabulin complex
Structural highlights
FunctionTBA1B_PIG Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain. Publication Abstract from PubMedMicrotubules, composed of alphabeta-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 beta-tubulin and only one site on alpha-tubulin, hinting that compounds binding to alpha-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 alpha-tubulin. We find that cevipabulin at this site pushes the alphaT5 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 alpha-tubulin and shed light on the development of tubulin degraders as a new generation of antimicrotubule drugs targeting this novel site. Cevipabulin-tubulin complex reveals a novel agent binding site on alpha-tubulin with tubulin degradation effect.,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 Sci Adv. 2021 May 19;7(21):eabg4168. doi: 10.1126/sciadv.abg4168. Print 2021 May. PMID:34138737[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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