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-Structure paper
タイトル | Structural and Biochemical Insights into the Mechanism of Action of the Clinical USP1 Inhibitor, KSQ-4279. |
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ジャーナル・号・ページ | J Med Chem, Vol. 67, Issue 17, Page 15557-15568, Year 2024 |
掲載日 | 2024年9月12日 |
著者 | Martin Luke Rennie / Mehmet Gundogdu / Connor Arkinson / Steven Liness / Sheelagh Frame / Helen Walden / |
PubMed 要旨 | 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 ...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. |
リンク | J Med Chem / PubMed:39190802 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.7 - 3.2 Å |
構造データ | EMDB-50316, PDB-9fci: EMDB-50317, PDB-9fcj: |
化合物 | ChemComp-ZN: PDB-1ib8: ChemComp-JDA: ChemComp-HOH: |
由来 |
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キーワード | HYDROLASE / INHIBITOR / DEUBIQUITINASE / COMPLEX / ENZYME-SUBSTRATE |