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Mitoquinone Inactivates Mitochondrial Chaperone TRAP1 by Blocking the Client Binding Site

Cite this: J. Am. Chem. Soc. 2021, 143, 47, 19684–19696
Publication Date (Web):November 10, 2021
https://doi.org/10.1021/jacs.1c07099
Copyright © 2021 American Chemical Society
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    Abstract

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    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.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.1c07099.

    • Experimental section, synthetic protocols, and molecular characterization of compounds; drug-induced aggregation of thermal denaturation of TRAP1, TRAP1 sequence alignment, and molecular interaction of TRAP1 residues with MitoQ; effects of antioxidant linker length on TRAP1, conformational change of TRAP1 induced by MitoQ, SAXS analysis, SIRT3-TRAP1 interaction, TRAP1-interactome analysis, and in vitro and in vivo anticancer activity of MitoQ and SB-series drugs; cytotoxic activity of various TPP compounds on normal and cancer cells; and statistics for the crystal structure of zTRAP1-MitoQ-AMPPNP (PDF)

    • Raw data for proteomic analysis of TRAP1 interactomes (XLSX)

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    This article is cited by 4 publications.

    1. Soosung Kang, Byoung Heon Kang. Structure, Function, and Inhibitors of the Mitochondrial Chaperone TRAP1. Journal of Medicinal Chemistry 2022, 65 (24) , 16155-16172. https://doi.org/10.1021/acs.jmedchem.2c01633
    2. Xiaoxia Cheng, Dong Feng, Junyu Lv, Xiaoman Cui, Yichen Wang, Qun Wang, Lei Zhang. Application Prospects of Triphenylphosphine-Based Mitochondria-Targeted Cancer Therapy. Cancers 2023, 15 (3) , 666. https://doi.org/10.3390/cancers15030666
    3. Versha Tripathi, Pooja Jaiswal, Khageswar Sahu, Shovan Kumar Majumder, Dharmendra Kashyap, Hem Chandra Jha, Amit Kumar Dixit, Hamendra Singh Parmar. Repurposing of metabolic drugs and mitochondrial modulators as an emerging class of cancer therapeutics with a special focus on breast cancer. Advances in Cancer Biology - Metastasis 2022, 6 , 100065. https://doi.org/10.1016/j.adcanc.2022.100065
    4. Laura A. Wengert, Sarah J. Backe, Dimitra Bourboulia, Mehdi Mollapour, Mark R. Woodford. TRAP1 Chaperones the Metabolic Switch in Cancer. Biomolecules 2022, 12 (6) , 786. https://doi.org/10.3390/biom12060786
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