Open AccessDiscovery of Small Molecule Antagonists of the USP5 Zinc Finger Ubiquitin-Binding Domain
Author(s) -
Mandeep Mann,
Ivan Franzoni,
Renato Ferreira de Freitas,
W. Tempel,
Scott Houliston,
Leanna Smith,
Masoud Vedadi,
C.H. Arrowsmith,
Rachel Harding,
Matthieu Schapira
Publication year - 2019
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.9b00988
Subject(s) - ubiquitin , chemistry , allosteric regulation , zinc finger , function (biology) , microbiology and biotechnology , biochemistry , computational biology , enzyme , gene , biology , transcription factor
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.
Accelerating Research
Robert Robinson Avenue,
Oxford Science Park, Oxford
OX4 4GP, United Kingdom
Address
John Eccles HouseRobert Robinson Avenue,
Oxford Science Park, Oxford
OX4 4GP, United Kingdom