Heat shock protein 90 (Hsp90) family proteins are molecular chaperones that modulate the functions of various substrate proteins (clients) implicated in pro-tumorigenic pathways. In this study, the mitochondria-targeted antioxidant mitoquinone (MitoQ) was identified as a potent inhibitor of mitochondrial Hsp90, known as a tumor necrosis factor receptor-associated protein 1 (TRAP1). Structural analyses revealed an asymmetric bipartite interaction between MitoQ and the previously unrecognized drug binding sites located in the middle domain of TRAP1, believed to be a client binding region. MitoQ effectively competed with TRAP1 clients, and MitoQ treatment facilitated the identification of 103 TRAP1-interacting mitochondrial proteins in cancer cells. MitoQ and its redox-crippled SB-U014/SB-U015 exhibited more potent anticancer activity in vitro and in vivo than previously reported mitochondria-targeted TRAP1 inhibitors. The findings indicate that targeting the client binding site of Hsp90 family proteins offers a novel strategy for the development of potent anticancer drugs.

中文翻译：

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米托醌通过阻断客户端结合位点使线粒体伴侣 TRAP1 失活

热休克蛋白 90 (Hsp90) 家族蛋白是分子伴侣，可调节与促肿瘤发生途径有关的各种底物蛋白（客户）的功能。在这项研究中，线粒体靶向抗氧化剂米托醌 (MitoQ) 被鉴定为线粒体 Hsp90 的有效抑制剂，称为肿瘤坏死因子受体相关蛋白 1 (TRAP1)。结构分析揭示了 MitoQ 与以前未被识别的位于 TRAP1 中间结构域的药物结合位点之间的不对称二分相互作用，该位点被认为是客户结合区域。MitoQ 有效地与 TRAP1 客户竞争，MitoQ 治疗促进了癌细胞中 103 个与 TRAP1 相互作用的线粒体蛋白的鉴定。MitoQ 及其氧化还原缺陷的 SB-U014/SB-U015 表现出更有效的抗癌活性在体外和体内比以前报道的线粒体靶向 TRAP1 抑制剂。研究结果表明，靶向 Hsp90 家族蛋白的客户结合位点为开发有效的抗癌药物提供了一种新策略。