Mitoquinone Inactivates Mitochondrial Chaperone TRAP1 by Blocking the Client Binding Site

Nam Gu Yoon, Hakbong Lee, So Yeon Kim, Sung Hu, Darong Kim, Sujae Yang, Ki Bum Hong, Ji Hoon Lee, Soosung Kang, Byung Gyu Kim, Kyungjae Myung, Changwook Lee, Byoung Heon Kang

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


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.

Original languageEnglish
Pages (from-to)19684-19696
Number of pages13
JournalJournal of the American Chemical Society
Issue number47
StatePublished - 1 Dec 2021

Bibliographical note

Funding Information:
This work was supported by grants from the National Research Foundation of Korea (NRF-2019R1A2C2086618; NRF-2018R1A5A1024340; NRF-2021R1A2C2009550; and NRF-2021M3A9G8022413) funded by the Korea government (MSIT) and the Tech Incubator Program for Startup Korea (TIPS) program (S2783310) funded by the Korea government (MSS). B.G.K. and K.M. were supported by an Institute for Basic Science grant (IBS-R022-D1)

Publisher Copyright:
© 2021 American Chemical Society.


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