Allosteric Regulation of Hsp90α's Activity by Small Molecules Targeting the Middle Domain of the Chaperone
Allosteric Regulation of Hsp90α's Activity by Small Molecules Targeting the Middle Domain of the Chaperone
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针对伴侣分子中域的小分子对 Hsp90α 活性的变构调节
DOI：
10.1016/j.isci.2020.100857
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发表时间：
2020
期刊：
影响因子：
5.8
通讯作者：
Zhang Naixia
中科院分区：
文献类型：
--
作者：
Zhou Chen;Zhang Chi;Zhu Hongwen;Liu Zhijun;Su Haixia;Zhang Xianglei;Chen Tingting;Zhong Yan;Hu Huifang;Xiong Muya;Zhou Hu;Xu Yechun;Zhang Ao;Zhang Naixia
Hsp 90是抗癌药物开发的靶点。由ATP/ADP和辅助分子伴侣调节的构象事件以及分子伴侣周期定时都是Hsp 90的全功能展示所必需的。干扰任何一个构象事件或周期定时将下调Hsp 90的功能。本文首次开发了以Hsp 90 α中间结构域（Hsp 90 M）为靶点的非共价别构调节剂（SOMCL-16- 171和SOMCL-16-175）。然后应用多种技术来表征两种活性化合物与Hsp 90 α之间的相互作用。Hsp 90 M的两个环和一个α-螺旋（F349-N360、K443-E451和D372-G387）负责识别SOMCL-16- 171和SOMCL-16-175。同时，SOMCL-16- 171和SOMCL-16- 175与Hsp 90 α M的结合对Hsp 90 α N端结构域的结构和功能具有变构调节作用。最后，进行细胞测定以评估SOMCL-16-175的细胞活性，结果表明SOMCL-16- 175使Hsp 90的客户蛋白不稳定并降低细胞活力。
Hsp90 is a target for anti-cancer drug development. Both the conformational events tuned by ATP/ADP and co-chaperones and the chaperoning cycle timing are required for Hsp90's fully functional display. Interfering with either one of the conformational events or the cycle timing will down-regulate Hsp90's function. In this manuscript, non-covalent allosteric modulators(SOMCL-16-171andSOMCL-16-175) targeting Hsp90α's middle domain (Hsp90M) were developed for the first time. Multiple techniques were then applied to characterize the interactions between two active compounds and Hsp90α. Two loops and one α-helix (F349-N360, K443-E451, and D372-G387) in Hsp90M were identified responsible for the recognition ofSOMCL-16-171andSOMCL-16-175. Meanwhile, the binding ofSOMCL-16-171andSOMCL-16-175to Hsp90M was demonstrated to allosterically modulate the structure and function of Hsp90α's N-terminal domain. Finally, cellular assays were conducted to evaluate the cellular activity ofSOMCL-16-175, and the results indicate thatSOMCL-16-175destabilizes Hsp90's client proteins and reduces cell viability.