AI Article Synopsis
- USP5 is a deubiquitinase linked to various diseases, including cancer, but specific chemical probes targeting it have not been developed.
- Researchers have advanced a series of chemicals that inhibit USP5's activity by binding to its C-terminal ubiquitin-binding site in a zinc-finger ubiquitin binding domain.
- Their study identified a compound that selectively binds to USP5 with a strong affinity while also blocking its activity on a di-ubiquitin substrate, paving the way for future research on USP5’s role in cellular functions.
Article Abstract
USP5 is a deubiquitinase that has been implicated in a range of diseases, including cancer, but no USP5-targeting chemical probe has been reported to date. Here, we present the progression of a chemical series that occupies the C-terminal ubiquitin-binding site of a poorly characterized zinc-finger ubiquitin binding domain (ZnF-UBD) of USP5 and competitively inhibits the catalytic activity of the enzyme. Exploration of the structure-activity relationship, complemented with crystallographic characterization of the ZnF-UBD bound to multiple ligands, led to the identification of , which binds to the USP5 ZnF-UBD with a of 2.8 μM and is selective over nine proteins containing structurally similar ZnF-UBD domains. inhibits the USP5 catalytic cleavage of a di-ubiquitin substrate in an assay. This study provides a chemical and structural framework for the discovery of a chemical probe to delineate USP5 function in cells.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/acs.jmedchem.1c00889 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!