9FCI

USP1 bound to KSQ-4279 and ubiquitin conjugated to FANCD2 (focused refinement)

This is a non-PDB format compatible entry.

Summary for 9FCI

• Entry DOI: 10.2210/pdb9fci/pdb
• Related: 7ZH3 7ZH4 9FCJ
• EMDB information: 50316
• Descriptor: Ubiquitin carboxyl-terminal hydrolase 1, Polyubiquitin-C, ZINC ION, ... (4 entities in total)
• Functional Keywords: inhibitor, deubiquitinase, complex, enzyme-substrate, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 97865.34

Authors

Rennie, M.L.,Gundogdu, M.,Walden, H. (deposition date: 2024-05-15, release date: 2024-09-04, Last modification date: 2024-09-25)

Primary citation

Rennie, M.L.,Gundogdu, M.,Arkinson, C.,Liness, S.,Frame, S.,Walden, H.
Structural and Biochemical Insights into the Mechanism of Action of the Clinical USP1 Inhibitor, KSQ-4279.
J.Med.Chem., 67:15557-15568, 2024

PubMed 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.

PubMed: 39190802
DOI: 10.1021/acs.jmedchem.4c01184

Experimental method

ELECTRON MICROSCOPY (3.2 Å)