Mitoquinone Inactivates Mitochondrial Chaperone TRAP1 by Blocking the Client Binding Site.
J Am Chem Soc
; 143(47): 19684-19696, 2021 12 01.
Article
en En
| MEDLINE
| ID: mdl-34758612
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 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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Compuestos Organofosforados
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Ubiquinona
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Proteínas HSP90 de Choque Térmico
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Neoplasias
/
Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Humans
Idioma:
En
Revista:
J Am Chem Soc
Año:
2021
Tipo del documento:
Article
País de afiliación:
Corea del Sur