Discovery of Small Molecule Antagonists of the USP5 Zinc Finger Ubiquitin-Binding Domain.
USP5 disassembles unanchored polyubiquitin chains to recycle free monoubiquitin, and is one of the 12 ubiquitin specific proteases featuring a zinc finger ubiquitin-binding domain (ZnF-UBD). This distinct structural module has been associated with substrate positioning or allosteric modulation of catalytic activity, but its cellular function remains unclear. We screened a ... chemical library focused on the ZnF-UBD of USP5, crystallized hits in complex with the protein, and generated a preliminary structure-activity relationship, which enables the development of more potent and selective compounds. This work serves as a framework for the discovery of a chemical probe to delineate the function of USP5 ZnF-UBD in proteasomal degradation and other ubiquitin signaling pathways in health and disease.
Mesh Terms:
Binding Sites, Crystallography, X-Ray, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Endopeptidases, Magnetic Resonance Spectroscopy, Protease Inhibitors, Protein Domains, Small Molecule Libraries, Structure-Activity Relationship, Surface Plasmon Resonance, Ubiquitin, Zinc Fingers
Binding Sites, Crystallography, X-Ray, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Endopeptidases, Magnetic Resonance Spectroscopy, Protease Inhibitors, Protein Domains, Small Molecule Libraries, Structure-Activity Relationship, Surface Plasmon Resonance, Ubiquitin, Zinc Fingers
J. Med. Chem.
Date: Dec. 27, 2018
PubMed ID: 31663737
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