Pironetin Binds Covalently to αCys316 and Perturbs a Major Loop and Helix of α-Tubulin to Inhibit Microtubule Formation
Pironetin Binds Covalently to αCys316 and Perturbs a Major Loop and Helix of α-Tubulin to Inhibit Microtubule Formation
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DOI：
10.1016/j.jmb.2016.06.023
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发表时间：
2016-07-31
影响因子：
5.6
通讯作者：
Steinmetz, Michel O.
中科院分区：
文献类型：
--
作者：
Prota, Andrea E.;Setter, Jocelyn;Steinmetz, Michel O.
微管靶向剂是用于治疗癌症患者的化疗中最强大的药物之一。吡柔酮是一种天然产物，通过结合并有效抑制微管蛋白组装成微管而显示出有希望的抗癌特性;然而，其分子作用机制仍然不清楚。在这里，我们解决了微管蛋白-pironetin复合物的晶体结构，并发现该化合物共价结合到α-微管蛋白的Cys 316。该结构进一步揭示，pironetin扰乱α-微管蛋白的17环和螺旋H8。由于这两个元素是必不可少的建立纵向微管蛋白接触微管，这一结果解释了如何pironetin抑制微管的形成。总之，我们的数据定义了α-微管蛋白上的pironetin结合位点的分子细节，从而为合理设计具有改进活性谱的pironetin变体提供了有希望的基础。它们进一步扩展了我们对天然产物进化的策略的知识，以靶向和干扰微管细胞骨架。(C)2016爱思唯尔有限公司版权所有。
Microtubule-targeting agents are among the most powerful drugs used in chemotherapy to treat cancer patients. Pironetin is a natural product that displays promising anticancer properties by binding to and potently inhibiting tubulin assembly into microtubules; however, its molecular mechanism of action remained obscure. Here, we solved the crystal structure of the tubulin-pironetin complex and found that the compound covalently binds to Cys316 of alpha-tubulin. The structure further revealed that pironetin perturbs the 17 loop and helix H8 of a-tubulin. Since both these elements are essential for establishing longitudinal tubulin contacts in microtubules, this result explains how pironetin inhibits the formation of microtubules. Together, our data define the molecular details of the pironetin binding site on alpha-tubulin and thus offer a promising basis for the rational design of pironetin variants with improved activity profiles. They further extend our knowledge on strategies evolved by natural products to target and perturb the microtubule cytoskeleton. (C) 2016 Elsevier Ltd. All rights reserved.