Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
Department of Clinical Research, West China Hospital, Sichuan University, Chengdu, China.
FEBS Lett. 2021 Jan;595(2):195-205. doi: 10.1002/1873-3468.14003. Epub 2021 Jan 10.
Tubulin 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 Å. 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 and Asn329 . Our studies provided the structural basis for designing novel tubulin vinca-domain ligands.
长春碱类微管蛋白结合物可抑制微管聚合，导致有丝分裂细胞死亡，其对多种癌症类型的潜在疗效已得到证实。然而，由于耐药性和毒性，仍需要开发新型长春碱类微管蛋白结合物。在这项研究中，我们测定了长春瑞滨、YXD 和重楼苷 A 与微管蛋白在 2.5 Å分辨率下的复合物晶体结构。此外，我们还重新解析了所有之前发表的长春碱结合位点的高分辨率晶体结构，以揭示与微管蛋白相互作用的长春碱类结合物的关键残基和分子机制。此外，我们通过引入仲胺基团设计了推测的新型三唑并嘧啶衍生物，与 Asp179 和 Asn329 建立盐桥和氢键相互作用。我们的研究为设计新型微管蛋白长春碱类结合物提供了结构基础。
