Mitoquinone Inactivates Mitochondrial Chaperone TRAP1 by Blocking the Client Binding Site

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 mitochon...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2021-12, Vol.143 (47), p.19684-19696
Main Authors: 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
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Binding Sites
HeLa Cells
HSP90 Heat-Shock Proteins - antagonists & inhibitors
HSP90 Heat-Shock Proteins - chemistry
Humans
Mice
Mice, Nude
Neoplasms - drug therapy
Organophosphorus Compounds - pharmacology
Organophosphorus Compounds - therapeutic use
Ubiquinone - analogs & derivatives
Ubiquinone - pharmacology
Ubiquinone - therapeutic use
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.1c07099