DSSR-PyMOL cartoon-block schematics: PDB entry 8a9k

PDB-id

8a9k; DSSR-derived features in text and JSON formats

Class

hydrolase

Method

cryo-EM (2.85 Å)

Summary

cryo-EM structure of usp1-uaf1 bound to fanci and mono-ubiquitinated fancd2 with ml323 (consensus reconstruction)

Reference

Rennie ML, Arkinson C, Chaugule VK, Walden H (2022): "Cryo-EM reveals a mechanism of USP1 inhibition through a cryptic binding site." Sci Adv, 8, eabq6353. doi: 10.1126/sciadv.abq6353.

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.