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TitleCryo-EM reveals a mechanism of USP1 inhibition through a cryptic binding site.
Journal, issue, pagesSci Adv, Vol. 8, Issue 39, Page eabq6353, Year 2022
Publish dateSep 30, 2022
AuthorsMartin L Rennie / Connor Arkinson / Viduth K Chaugule / Helen Walden /
PubMed AbstractRepair 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 ...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.
External linksSci Adv / PubMed:36170365 / PubMed Central
MethodsEM (single particle)
Resolution2.49 - 2.85 Å
Structure data

EMDB-14719: FANCD2 Middle and C-terminal domains with USP1-NTE (focused refinement)
Method: EM (single particle) / Resolution: 2.61 Å

14720

7zh3

EMDB-14720, PDB-7zh3:
USP1 bound to ubiquitin conjugated to FANCD2 (focused refinement)
Method: EM (single particle) / Resolution: 2.5 Å

14721

7zh4

EMDB-14721, PDB-7zh4:
USP1 bound to ML323 and ubiquitin conjugated to FANCD2 (focused refinement)
Method: EM (single particle) / Resolution: 2.49 Å

14722

8a9k

EMDB-14722, PDB-8a9k:
Cryo-EM structure of USP1-UAF1 bound to FANCI and mono-ubiquitinated FANCD2 with ML323 (consensus reconstruction)
Method: EM (single particle) / Resolution: 2.85 Å

15284

8a9j

EMDB-15284, PDB-8a9j:
Cryo-EM structure of USP1-UAF1 bound to FANCI and mono-ubiquitinated FANCD2 without ML323 (consensus reconstruction)
Method: EM (single particle) / Resolution: 2.8 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-HOH:
WATER

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

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsHYDROLASE / Deubiquitinase / Complex / Enzyme-Substrate / Inhibitor

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