8A9K

Cryo-EM structure of USP1-UAF1 bound to FANCI and mono-ubiquitinated FANCD2 with ML323 (consensus reconstruction)

Summary for 8A9K

• Entry DOI: 10.2210/pdb8a9k/pdb
• Related: 7ZH3 7ZH4 8A9J
• EMDB information: 14720 14721 14722
• Descriptor: Fanconi anemia group I protein, Fanconi anemia group D2 protein, Polyubiquitin-C, ... (8 entities in total)
• Functional Keywords: deubiquitinase, complex, enzyme-substrate, inhibitor, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 7
• Total formula weight: 501454.53

Authors

Rennie, M.L.,Walden, H. (deposition date: 2022-06-28, release date: 2022-10-12, Last modification date: 2024-10-23)

Primary citation

Rennie, M.L.,Arkinson, C.,Chaugule, V.K.,Walden, H.
Cryo-EM reveals a mechanism of USP1 inhibition through a cryptic binding site.
Sci Adv, 8:eabq6353-eabq6353, 2022

PubMed 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.

PubMed: 36170365
DOI: 10.1126/sciadv.abq6353

Experimental method

ELECTRON MICROSCOPY (2.85 Å)