7cnn
vinorelbine in complex with tubulin
Structural highlights
FunctionTBB_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 PubMedTubulin vinca-domain ligands can inhibit microtubule polymerization, causing cell death in mitosis, and their potential against multiple cancer types has been demonstrated. However, due to drug resistance and toxicities, development of novel vinca-domain ligands is still needed. In this study, we determined the high-resolution crystal structures of vinorelbine, YXD, and Phomopsin A in complex with tubulin at 2.5 A. Additionally, we recapitulated all previously published high-resolution crystal structures of the vinca binding site to reveal critical residues and the molecular mechanism of vinca-domain ligands interacting with tubulin. Furthermore, we designed putatively novel triazolopyrimidine derivatives by introducing secondary amine groups to establish salt-bridge and H-bond interactions with Asp179(beta1) and Asn329(alpha2) . Our studies provided the structural basis for designing novel tubulin vinca-domain ligands. The high-resolution X-ray structure of vinca-domain inhibitors of microtubules provides a rational approach for drug design.,Chengyong W, Jinghong X, Yanyan W, Qing-Jie X, Lingling M, Yuyan L, Hai C, Qian L, Quan Z, Bo S, Yuxi W FEBS Lett. 2021 Jan;595(2):195-205. doi: 10.1002/1873-3468.14003. Epub 2021 Jan , 10. PMID:33220079[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
