Structures of a diverse set of colchicine binding site inhibitors in complex with tubulin provide a rationale for drug discovery
Structures of a diverse set of colchicine binding site inhibitors in complex with tubulin provide a rationale for drug discovery
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与微管蛋白复合的多种秋水仙碱结合位点抑制剂的结构为药物发现提供了理论基础
DOI：
10.1111/febs.13555
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发表时间：
2016-01-01
期刊：
影响因子：
5.4
通讯作者：
Yang, Jinliang
中科院分区：
文献类型：
--
作者：
Wang, Yuxi;Zhang, Hang;Yang, Jinliang
微管是微管蛋白异源二聚体的动态组装，已被公认为是癌症化疗的极具吸引力的靶点。许多试剂都能与微管蛋白结合并干扰微管的组装。秋水仙碱结合位点抑制剂(CBSI)虽然有很长的研究历史，但到目前为止还没有作为抗癌药物进入商业阶段。我们确定了与一系列结构不同的CBSI(来昔布林、诺可达唑、普利布林和维坦替尼)复合的微管蛋白的结构，其中诺可达唑和维坦替尼都是同时针对肿瘤相关激酶和微管的双功能抑制剂。高分辨结构揭示了这些配体与微管蛋白之间的详细相互作用。我们的结果表明，CBSI的结合模式不同于以往的对接模型，突显了晶体结构信息在基于结构的药物设计中的重要性。提出了一个真正的基于结构的药效团来合理化秋水仙碱领域中CBSI的关键共同作用。我们的研究为开发秋水仙素结合部位的新型抗癌药物提供了坚实的结构基础。数据库已将来昔布林、诺可达唑、普利布林和维坦替尼与微管蛋白络合的原子坐标和结构因子分别登记在蛋白质数据库中，登录号为和。
Microtubules are dynamic assemblies of -tubulin heterodimers and have been recognized as highly attractive targets for cancer chemotherapy. A broad range of agents bind to tubulin and interfere with microtubule assembly. Despite having a long history of characterization, colchicine binding site inhibitors (CBSIs) have not yet reached the commercial phase as anti-cancer drugs to date. We determined the structures of tubulin complexed with a set of structurally diverse CBSIs (lexibulin, nocodazole, plinabulin and tivantinib), among which nocodazole and tivantinib are both binary-function inhibitors targeting cancer-related kinases and microtubules simultaneously. High resolution structures revealed the detailed interactions between these ligands and tubulin. Our results showed that the binding modes of the CBSIs were different from previous docking models, highlighting the importance of crystal structure information in structure-based drug design. A real structure-based pharmacophore was proposed to rationalize key common interactions of the CBSIs at the colchicine domain. Our studies provide a solid structural basis for developing new anti-cancer agents for the colchicine binding site.DatabaseThe atomic coordinates and structure factors for tubulin complexed with lexibulin, nocodazole, plinabulin and tivantinib have been deposited in the Protein Data Bank under accession codes , , and , respectively.