9FCJ

USP1 bound to ML323 and ubiquitin conjugated to FANCD2 (ordered subset, focused refinement)

9FCJ の概要

• エントリーDOI: 10.2210/pdb9fcj/pdb
• 関連するPDBエントリー: 7ZH3 7ZH4 9FCI
• EMDBエントリー: 50317
• 分子名称: Polyubiquitin-C, Ubiquitin carboxyl-terminal hydrolase 1, ZINC ION, ... (5 entities in total)
• 機能のキーワード: inhibitor, deubiquitinase, complex, enzyme-substrate, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 97715.28

構造登録者

Rennie, M.L.,Gundogdu, M.,Walden, H. (登録日: 2024-05-15, 公開日: 2024-09-04, 最終更新日: 2024-09-25)

主引用文献

Rennie, M.L.,Gundogdu, M.,Arkinson, C.,Liness, S.,Frame, S.,Walden, H.
Structural and Biochemical Insights into the Mechanism of Action of the Clinical USP1 Inhibitor, KSQ-4279.
J.Med.Chem., 67:15557-15568, 2024

PubMed Abstract: 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.

PubMed: 39190802
DOI: 10.1021/acs.jmedchem.4c01184

実験手法

ELECTRON MICROSCOPY (2.7 Å)