Structural and Biochemical Insights into the Mechanism of Action of the Clinical USP1 Inhibitor, KSQ-4279
Open accessPublished version of a preprint
Abstract
DNA damage triggers cell signaling cascades that mediate repair. This signaling is frequently dysregulated in cancers. The proteins that mediate this signaling are potential targets for therapeutic intervention. Ubiquitin-specific protease 1 (USP1) is one such target, with small-molecule inhibitors already in clinical trials. Here, we use biochemical assays and cryo-electron microscopy (cryo-EM) to study the clinical USP1 inhibitor, KSQ-4279 (RO7623066), and compare this to the well-established tool compound, ML323. We find that KSQ-4279 binds to the same cryptic site of USP1 as ML323 but disrupts the protein structure in subtly different ways. Inhibitor binding drives a substantial increase in thermal stability of USP1, which may be mediated through the inhibitors filling a hydrophobic tunnel-like pocket in USP1. Our results contribute to the understanding of the mechanism of action of USP1 inhibitors at the molecular level.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
ColabFold - Making protein folding accessible to all
Mirdita, M., Schütze, K., Moriwaki, Y., Heo, L., Ovchinnikov, S., & Steinegger, M. (2021) · doi:10.1101/2021.08.15.456425 · Cited by 9,391 · see citing works
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- Authors
- Rennie, M. L., Gundogdu, M., Arkinson, C., Liness, S., Frame, S., & Walden, H.
- Affiliations
- University of Glasgow (GB)
- University of Dundee (GB)
- Corresponding author
- Rennie, Martin Luke
- Walden, Helen
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2024-08-27
- Volume
- 67
- Issue
- 17
- Pages
- 15557-15568
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC11403619
- OpenAlex
- W4401903557
- Cited by
- 27
- References
- 2
- Citations by year
- 2026: 12 · 2025: 15
- FWCI
- 3.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- Discovery Research Portal (University of Dundee) (submittedVersion, cc-by)
- Funders
- Research Councils UK (MR/W025256/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- USP1, cryptic binding sites, protein thermal stability, DNA damage signaling, DNA repair, inhibitor binding mechanism, protein structure
- MeSH terms
- Humans, Models, Molecular, Protease Inhibitors, Structure-Activity Relationship, Cryoelectron Microscopy, Ubiquitin-Specific Proteases
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