7EXP

Crystal structure of zebrafish TRAP1 with AMPPNP and MitoQ

Summary for 7EXP

• Entry DOI: 10.2210/pdb7exp/pdb
• Descriptor: TNF receptor-associated protein 1, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: trap1, hsp90, mitoquinone, mitoq, chaperone
• Biological source: Danio rerio (Zebrafish, Brachydanio rerio)
• Total number of polymer chains: 2
• Total formula weight: 149891.33

Authors

Lee, H.,Yoon, N.G.,Kang, B.H.,Lee, C. (deposition date: 2021-05-28, release date: 2022-01-05, Last modification date: 2025-09-17)

Primary citation

Yoon, N.G.,Lee, H.,Kim, S.Y.,Hu, S.,Kim, D.,Yang, S.,Hong, K.B.,Lee, J.H.,Kang, S.,Kim, B.G.,Myung, K.,Lee, C.,Kang, B.H.
Mitoquinone Inactivates Mitochondrial Chaperone TRAP1 by Blocking the Client Binding Site.
J.Am.Chem.Soc., 143:19684-19696, 2021

PubMed 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 and 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.

PubMed: 34758612
DOI: 10.1021/jacs.1c07099

Experimental method

X-RAY DIFFRACTION (2.297 Å)