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5N9R

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

Summary for 5N9R
Entry DOI10.2210/pdb5n9r/pdb
Related5N9T
DescriptorUbiquitin carboxyl-terminal hydrolase 7, SULFATE ION, GLYCEROL, ... (6 entities in total)
Functional Keywordsusp7, reversible, inhibitor, selective, hydrolase
Biological sourceHomo sapiens (Human)
Cellular locationNucleus : Q93009
Total number of polymer chains2
Total formula weight84621.24
Authors
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. (deposition date: 2017-02-27, release date: 2017-12-06, Last modification date: 2024-01-17)
Primary citationGavory, 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
Cited by
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
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.23 Å)
Structure validation

226707

數據於2024-10-30公開中

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