Abstract：
:USP7 is a deubiquitinating enzyme that plays a pivotal role in multiple oncogenic pathways and therefore is a desirable target for new anti-cancer therapies. However, the lack of structural information about the USP7-inhibitor interactions has been a critical gap in the development of potent inhibitors. USP7 is unique among USPs in that its active site is catalytically incompetent, and is postulated to rearrange into a productive conformation only upon binding to ubiquitin. Surprisingly, we found that ubiquitin alone does not induce an active conformation in solution. Using a combination of nuclear magnetic resonance, mass spectrometry, computational modeling, and cell-based assays, we found that DUB inhibitors P22077 and P50429 covalently modify the catalytic cysteine of USP7 and induce a conformational switch in the enzyme associated with active site rearrangement. This work represents the first experimental insights into USP7 activation and inhibition and provides a structural basis for rational development of potent anti-cancer therapeutics.
journal_name
Cell Chem Bioljournal_title
Cell chemical biologyauthors
Pozhidaeva A,Valles G,Wang F,Wu J,Sterner DE,Nguyen P,Weinstock J,Kumar KGS,Kanyo J,Wright D,Bezsonova Idoi
10.1016/j.chembiol.2017.09.004subject
Has Abstractpub_date
2017-12-21 00:00:00pages
1501-1512.e5issue
12eissn
2451-9456issn
2451-9448pii
S2451-9456(17)30330-6journal_volume
24pub_type
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