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.
Pubmed ID: 29056420 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This monoclonal targets β-Actin
View all literature mentionsThis monoclonal targets detection of MDM2, MDM2 p60 cleavage product and p53-MDM2 complexes
View all literature mentionsThis monoclonal targets UHRF1 (G-2)
View all literature mentionsThis monoclonal targets DNMT1 (D63A6) XP Rabbit mAb
View all literature mentionsProvides pre-calculated evolutionary conservation profiles for proteins of known structure in the PDB. Enables flexibility in setting the parameters of the calculation, and accepts optional uploads of atomic coordinates, multiple sequence alignments, and phylogenetic trees for use in the calculation of conservation profiles.
View all literature mentionsA collection of both commercial and noncommercial software products which includes: Mascot Distiller, Mascot Parser, and Mascot Server. Mascot Distiller is commercial and provides a single interface to process raw data into de-isotoped peak lists. This tool can also be used for the easy distribution of search and quantitative results to colleagues. The non-commercial Mascot Parser software provides an API (Application Programmer Interface) that makes it easier to access search results written in C++, Java, Python and Perl. Mascot Server is non-commercial, and is a collection of peptide mass fingerprints as well as a MS/MS database. A selection of popular sequence databases are available online and include SwissProt, NCBInr, and the EST divisions of EMBL. This server is best used for evaluating and searching for smaller data sets.
View all literature mentionsInteractive application for data analysis and visualization in the form of plots. Its main feature is its usability and its simple graphical user interface. SciDAVis runs on GNU/Linux, Windows and MacOS X.
View all literature mentionsCell line HCT 116 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HEK293 is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line Jurkat E6.1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentions