7exp

Crystal structure of zebrafish TRAP1 with AMPPNP and MitoQ

spinqualitylabelsall models 7exp, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.297Å Ligands: 05M, ANP, CO, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. Mitoquinone Inactivates Mitochondrial Chaperone TRAP1 by Blocking the Client Binding Site.,Yoon NG, Lee H, Kim SY, Hu S, Kim D, Yang S, Hong KB, Lee JH, Kang S, Kim BG, Myung K, Lee C, Kang BH J Am Chem Soc. 2021 Dec 1;143(47):19684-19696. doi: 10.1021/jacs.1c07099. Epub, 2021 Nov 10. PMID:34758612 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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