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Mitoquinone Inactivates Mitochondrial Chaperone TRAP1 by Blocking the Client Binding Site
- Source :
- Journal of the American Chemical Society; December 2021, Vol. 143 Issue: 47 p19684-19696, 13p
- Publication Year :
- 2021
-
Abstract
- 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 vitroand in vivothan 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.
Details
- Language :
- English
- ISSN :
- 00027863 and 15205126
- Volume :
- 143
- Issue :
- 47
- Database :
- Supplemental Index
- Journal :
- Journal of the American Chemical Society
- Publication Type :
- Periodical
- Accession number :
- ejs58239868
- Full Text :
- https://doi.org/10.1021/jacs.1c07099