7ZH4
USP1 bound to ML323 and ubiquitin conjugated to FANCD2 (focused refinement)
Summary for 7ZH4
| Entry DOI | 10.2210/pdb7zh4/pdb |
| EMDB information | 14719 14720 14721 14722 |
| Descriptor | Ubiquitin-60S ribosomal protein L40, Ubiquitin carboxyl-terminal hydrolase 1, ZINC ION, ... (5 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 | 97715.28 |
| Authors | Rennie, M.L.,Walden, H. (deposition date: 2022-04-05, release date: 2022-10-12, Last modification date: 2024-07-24) |
| 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 Cited by 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: 36170365DOI: 10.1126/sciadv.abq6353 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.49 Å) |
Structure validation
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