1. Discovery of small molecule antagonists of the USP5 zinc finger ubiquitin-binding domain
- Author
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Ivan Franzoni, Cheryl H. Arrowsmith, Rachel Harding, Scott Houliston, M.K. Mann, Matthieu Schapira, Wolfram Tempel, and Renato Ferreira de Freitas
- Subjects
Zinc finger ,0303 health sciences ,Proteases ,Ubiquitin binding ,biology ,Chemistry ,Allosteric regulation ,Small molecule ,Chemical library ,Cell biology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Ubiquitin ,biology.protein ,030217 neurology & neurosurgery ,Function (biology) ,030304 developmental biology - Abstract
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.
- Published
- 2019