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Discovery of Small Molecule Antagonists of the USP5 Zinc Finger Ubiquitin-Binding Domain

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posted on 11.11.2019, 22:44 authored by Mandeep K. Mann, Ivan Franzoni, Renato Ferreira de Freitas, Wolfram Tempel, Scott Houliston, Leanna Smith, Masoud Vedadi, Cheryl H. Arrowsmith, Rachel J. Harding, Matthieu Schapira
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.

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