Discovery of small molecule antagonists of the USP5 zinc finger ubiquitin-binding domain
Discovery of small molecule antagonists of the USP5 zinc finger ubiquitin-binding domain
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.
Mann Mandeep K.、Franzoni Ivan、de Freitas Renato Ferreira、Tempel Wolfram、Houliston Scott、Schapira Matthieu、Arrowsmith Cheryl H.、Harding Rachel J.
University of Toronto, Structural Genomics Consortium, MaRS Centre||University of Toronto, Department of Pharmacology and ToxicologyUniversity of Toronto, Department of ChemistryUniversity of Toronto, Structural Genomics Consortium, MaRS CentreUniversity of Toronto, Structural Genomics Consortium, MaRS CentreUniversity Health NetworkUniversity of Toronto, Structural Genomics Consortium, MaRS Centre||University of Toronto, Department of Pharmacology and ToxicologyUniversity of Toronto, Structural Genomics Consortium, MaRS Centre||University Health NetworkUniversity of Toronto, Structural Genomics Consortium, MaRS Centre
药学生物科学研究方法、生物科学研究技术生物化学
Mann Mandeep K.,Franzoni Ivan,de Freitas Renato Ferreira,Tempel Wolfram,Houliston Scott,Schapira Matthieu,Arrowsmith Cheryl H.,Harding Rachel J..Discovery of small molecule antagonists of the USP5 zinc finger ubiquitin-binding domain[EB/OL].(2025-03-28)[2025-05-22].https://www.biorxiv.org/content/10.1101/676668.点此复制
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