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bioRxiv · 10.1101/676668

Discovery of small molecule antagonists of the USP5 zinc finger ubiquitin-binding domain

Mann, M. K.·Franzoni, I.·Ferreira de Freitas, R.·Tempel, W.·Houliston, S.·Arrowsmith, C. H.·Harding, R. J.·Schapira, M.
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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.

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Mann, M. K., Franzoni, I., Ferreira de Freitas, R., Tempel, W., Houliston, S., Arrowsmith, C. H., Harding, R. J., Schapira, M.. 2019-06-21. Discovery of small molecule antagonists of the USP5 zinc finger ubiquitin-binding domain. https://doi.org/10.1101/676668

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