RT Journal Article
SR Electronic
T1 Discovery of small molecule antagonists of the USP5 zinc finger ubiquitin-binding domain
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 676668
DO 10.1101/676668
A1 Mandeep K. Mann
A1 Ivan Franzoni
A1 Renato Ferreira de Freitas
A1 Wolfram Tempel
A1 Scott Houliston
A1 Cheryl H. Arrowsmith
A1 Rachel J. Harding
A1 Matthieu Schapira
YR 2019
UL http://biorxiv.org/content/early/2019/06/22/676668.abstract
AB USP5 disassembles unanchored polyubiquitin chains to recycle free mono-ubiquitin, and is one of twelve 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 signalling pathways in health and disease.BARBennett acceptance ratio;DUBdeubiquitinase;FEPfree energy perturbation;KDdissociation constant;SARstructure activity relationship;SDstandard deviation;SPRsurface plasmon resonance;Ububiquitin;UBAubiquitin associated domain;UBPubiquitin-binding domain;USPubiquitin specific protease;ZnF-UBDzinc finger ubiquitin-binding domain;5FW5-fluoro-tryptophan