USP7-Specific Inhibitors Target and Modify the Enzyme's Active Site via Distinct Chemical Mechanisms.
Cell Chem Biol
; 24(12): 1501-1512.e5, 2017 12 21.
Article
em En
| MEDLINE
| ID: mdl-29056420
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.
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Base de dados:
MEDLINE
Assunto principal:
Inibidores de Proteases
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Tiofenos
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Peptidase 7 Específica de Ubiquitina
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article