Mitoquinone Inactivates Mitochondrial Chaperone TRAP1 by Blocking the Client Binding Site
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- Mitoquinone Inactivates Mitochondrial Chaperone TRAP1 by Blocking the Client Binding Site
- Yoon, Nam Gu; Lee, Hakbong; Kim, So-Yeon; Hu, Sung; Kim, Darong; Yang, Sujae; Hong, Ki Bum; Lee, Ji Hoon; Kang, Soosung; Kim, Byung-Gyu; Myung, Kyungjae; Lee, Changwook; Kang, Byoung Heon
- Issue Date
- AMER CHEMICAL SOC
- JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, v.143, no.47, pp.19684 - 19696
- 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.
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