Cryo-EM reveals a mechanism of USP1 inhibition through a cryptic binding site

Rennie, M. L. , Arkinson, C., Chaugule, V. K. and Walden, H. (2022) Cryo-EM reveals a mechanism of USP1 inhibition through a cryptic binding site. Science Advances, 8(39), eabq6353. (doi: 10.1126/sciadv.abq6353) (PMID:36170365)

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Repair of DNA damage is critical to genomic integrity and frequently disrupted in cancers. Ubiquitin-specific protease 1 (USP1), a nucleus-localized deubiquitinase, lies at the interface of multiple DNA repair pathways and is a promising drug target for certain cancers. Although multiple inhibitors of this enzyme, including one in phase 1 clinical trials, have been established, their binding mode is unknown. Here, we use cryo–electron microscopy to study an assembled enzyme-substrate-inhibitor complex of USP1 and the well-established inhibitor, ML323. Achieving 2.5-Å resolution, with and without ML323, we find an unusual binding mode in which the inhibitor disrupts part of the hydrophobic core of USP1. The consequent conformational changes in the secondary structure lead to subtle rearrangements in the active site that underlie the mechanism of inhibition. These structures provide a platform for structure-based drug design targeting USP1.

Item Type:Articles
Additional Information:Funding: European Research Council (ERC-2015-CoG-681582) ICLUb consolidator grant to H.W. 13. Medical Research Council (MC_UU_120164/12) to H.W.
Glasgow Author(s) Enlighten ID:Rennie, Dr Martin and Chaugule, Dr Viduth and Arkinson, Connor and Walden, Professor Helen
Authors: Rennie, M. L., Arkinson, C., Chaugule, V. K., and Walden, H.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:Science Advances
Publisher:American Association for the Advancement of Science
ISSN (Online):2375-2548
Published Online:28 September 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Science Advances 8(39): eabq6353
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
302391Regulation of DNA interstrand crosslink repair by ubiquitin.Helen WaldenEuropean Research Council (ERC)681506Institute of Molecular, Cell & Systems Biology