5N9R

Crystal structure of USP7 in complex with a potent, selective and reversible small-molecule inhibitor

5N9R の概要

• エントリーDOI: 10.2210/pdb5n9r/pdb
• 関連するPDBエントリー: 5N9T
• 分子名称: Ubiquitin carboxyl-terminal hydrolase 7, SULFATE ION, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: usp7, reversible, inhibitor, selective, hydrolase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : Q93009
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 84621.24

構造登録者

Harrison, T.,Gavory, G.,O'Dowd, C.,Helm, M.,Flasz, I.,Arkoudis, E.,Dossang, A.,Hughes, C.,Cassidy, E.,McClelland, K.,Odrzywol, E.,Page, N.,Barker, O.,Miel, H. (登録日: 2017-02-27, 公開日: 2017-12-06, 最終更新日: 2024-01-17)

主引用文献

Gavory, G.,O'Dowd, C.R.,Helm, M.D.,Flasz, J.,Arkoudis, E.,Dossang, A.,Hughes, C.,Cassidy, E.,McClelland, K.,Odrzywol, E.,Page, N.,Barker, O.,Miel, H.,Harrison, T.
Discovery and characterization of highly potent and selective allosteric USP7 inhibitors.
Nat. Chem. Biol., 14:118-125, 2018

PubMed Abstract: Given the importance of ubiquitin-specific protease 7 (USP7) in oncogenic pathways, identification of USP7 inhibitors has attracted considerable interest. Despite substantial efforts, however, the development of validated deubiquitinase (DUB) inhibitors that exhibit drug-like properties and a well-defined mechanism of action has proven particularly challenging. In this article, we describe the identification, optimization and detailed characterization of highly potent (IC < 10 nM), selective USP7 inhibitors together with their less active, enantiomeric counterparts. We also disclose, for the first time, co-crystal structures of a human DUB enzyme complexed with small-molecule inhibitors, which reveal a previously undisclosed allosteric binding site. Finally, we report the identification of cancer cell lines hypersensitive to USP7 inhibition (EC < 30 nM) and demonstrate equal or superior activity in these cell models compared to clinically relevant MDM2 antagonists. Overall, these findings demonstrate the tractability and druggability of DUBs, and provide important tools for additional target validation studies.

PubMed: 29200206
DOI: 10.1038/nchembio.2528

実験手法

X-RAY DIFFRACTION (2.23 Å)