Insights into the Distinct Mechanisms of Action of Taxane and Non-Taxane Microtubule Stabilizers from Cryo-EM Structures
Insights into the Distinct Mechanisms of Action of Taxane and Non-Taxane Microtubule Stabilizers from Cryo-EM Structures
复制标题
DOI：
10.1016/j.jmb.2017.01.001
复制
发表时间：
2017-03-10
影响因子：
5.6
通讯作者：
Nogales, Eva
中科院分区：
文献类型：
--
作者：
Kellogg, Elizabeth H.;Hejab, Nisreen M. A.;Nogales, Eva
许多微管 (MT) 稳定剂 (MSA) 已证明或预测其作为抗癌药物的潜力，但具体情况还不清楚。其作用机制的结构基础仍然缺乏。我们获得了由紫杉烷位点结合剂紫杉醇和赞帕内酯以及 Peloruside 稳定的 MT 的高分辨率（3.9-4.2 埃）冷冻电子显微镜 (cryo-EM) 重建，其目标是 13-微管蛋白上独特的非紫杉烷口袋。我们发现每个分子对 MT 晶格结构都有独特的结构效应。 Peloruside 主要作用于横向接触，并对异源相互作用的“接缝”产生影响，强制形成更类似于同源（即非接缝）接触的构象，从而使 MT 晶格规则化。相反，紫杉醇或桑帕内酯的结合会诱导 MT 异质性。在双重结合 MT 中，peloruside 克服了紫杉醇结合引起的异质性。我们的结构分析说明了这些药物稳定 MT 晶格的独特机制，并且与可能使用 MSA 组合来调节 MT 活性和提高治疗潜力相关。 (C) 2017 年作者。由 Elsevier Ltd 出版。这是一篇遵循 CC BY-NC-ND 许可证 (http://creativecommons.org/licenses/by-nc-nd/4.0/) 的开放获取文章。
A number of microtubule (MT)-stabilizing lagents (MSAs) have demonstrated or predicted potential as anticancer agents, but a detailed. structural basis for their mechanism of action is still lacking. We have obtained high-resolution (3.9-4.2 angstrom) cryo-electron microscopy (cryo-EM) reconstructions of MTs stabilized by the taxane-site binders Taxol and zampanolide, and by peloruside, which targets a distinct, non-taxoid pocket on 13-tubulin. We find that each molecule has unique distinct structural effects on the MT lattice structure. Peloruside acts primarily at lateral contacts and has an effect on the "seam" of heterologous interactions, enforcing a conformation more similar to that of homologous (i.e., non-seam) contacts by which it regularizes the MT lattice. In contrast, binding of either Taxol or zampanolide induces MT heterogeneity. In doubly bound MTs, peloruside overrides the heterogeneity induced by Taxol binding. Our structural analysis illustrates distinct mechanisms of these drugs for stabilizing the MT lattice and is of relevance to the possible use of combinations of MSAs to regulate MT activity and improve therapeutic potential. (C) 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).