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Cryo-EM reveals a mechanism of USP1 inhibition through a cryptic binding site
Open accessPublished version of a preprint
Abstract
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.
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Metadata
- Authors
- Rennie, M. L., Arkinson, C., Chaugule, V. K., & Walden, H.
- Affiliations
- University of Glasgow (GB)
- Corresponding author
- Rennie, Martin L.
- Walden, Helen
- Venue
- Science Advances
- Published
- 2022-09-30
- Volume
- 8
- Issue
- 39
- Pages
- eabq6353-eabq6353
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC9519042
- OpenAlex
- W4297502041
- Cited by
- 40
- References
- 2
- Citations by year
- 2026: 8 · 2025: 20 · 2024: 7 · 2023: 3 · 2022: 2
- FWCI
- 2.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Science Advances (publishedVersion, cc-by-nc)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- Funders
- Wellcome Trust
- Diamond Light Source
- Medical Research Council (MR/W025256/1, MC_PC_17135, MC_UU_120164/12)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- USP1, deubiquitinase, cryptic binding sites, protein conformational change, active site rearrangement, DNA repair, structure-based drug design, cancer drug targets
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