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TitleStructural and Biochemical Insights into the Mechanism of Action of the Clinical USP1 Inhibitor, KSQ-4279.
Journal, issue, pagesJ Med Chem, Vol. 67, Issue 17, Page 15557-15568, Year 2024
Publish dateSep 12, 2024
AuthorsMartin Luke Rennie / Mehmet Gundogdu / Connor Arkinson / Steven Liness / Sheelagh Frame / Helen Walden /
PubMed AbstractDNA 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 ...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.
External linksJ Med Chem / PubMed:39190802 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 3.2 Å
Structure data

50316

9fci

EMDB-50316, PDB-9fci:
USP1 bound to KSQ-4279 and ubiquitin conjugated to FANCD2 (focused refinement)
Method: EM (single particle) / Resolution: 3.2 Å

50317

9fcj

EMDB-50317, PDB-9fcj:
USP1 bound to ML323 and ubiquitin conjugated to FANCD2 (ordered subset, focused refinement)
Method: EM (single particle) / Resolution: 2.7 Å

Chemicals

ChemComp-ZN:
Unknown entry

PDB-1ib8:
SOLUTION STRUCTURE AND FUNCTION OF A CONSERVED PROTEIN SP14.3 ENCODED BY AN ESSENTIAL STREPTOCOCCUS PNEUMONIAE GENE

ChemComp-JDA:
5-methyl-2-(2-propan-2-ylphenyl)-~{N}-[[4-(1,2,3-triazol-1-yl)phenyl]methyl]pyrimidin-4-amine

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsHYDROLASE / INHIBITOR / DEUBIQUITINASE / COMPLEX / ENZYME-SUBSTRATE

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