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

Autor: Mann MK; Structural Genomics Consortium, University of Toronto, MaRS Centre , South Tower, 101 College St., Suite 700 , Toronto , Ontario M5G 1L7 , Canada.; Department of Pharmacology and Toxicology , University of Toronto , 1 King's College Circle , Toronto , Ontario M5S 1A8 , Canada., Franzoni I; Department of Chemistry , University of Toronto , 80 St. George St. , Toronto , Ontario M5S 3H6 , Canada., de Freitas RF; Structural Genomics Consortium, University of Toronto, MaRS Centre , South Tower, 101 College St., Suite 700 , Toronto , Ontario M5G 1L7 , Canada., Tempel W; Structural Genomics Consortium, University of Toronto, MaRS Centre , South Tower, 101 College St., Suite 700 , Toronto , Ontario M5G 1L7 , Canada., Houliston S; University Health Network , 661 University Avenue , Toronto , Ontario M5G 2C4 , Canada., Smith L; Structural Genomics Consortium, University of Toronto, MaRS Centre , South Tower, 101 College St., Suite 700 , Toronto , Ontario M5G 1L7 , Canada., Vedadi M; Structural Genomics Consortium, University of Toronto, MaRS Centre , South Tower, 101 College St., Suite 700 , Toronto , Ontario M5G 1L7 , Canada.; Department of Pharmacology and Toxicology , University of Toronto , 1 King's College Circle , Toronto , Ontario M5S 1A8 , Canada., Arrowsmith CH; Structural Genomics Consortium, University of Toronto, MaRS Centre , South Tower, 101 College St., Suite 700 , Toronto , Ontario M5G 1L7 , Canada.; University Health Network , 661 University Avenue , Toronto , Ontario M5G 2C4 , Canada., Harding RJ; Structural Genomics Consortium, University of Toronto, MaRS Centre , South Tower, 101 College St., Suite 700 , Toronto , Ontario M5G 1L7 , Canada., Schapira M; Structural Genomics Consortium, University of Toronto, MaRS Centre , South Tower, 101 College St., Suite 700 , Toronto , Ontario M5G 1L7 , Canada.; Department of Pharmacology and Toxicology , University of Toronto , 1 King's College Circle , Toronto , Ontario M5S 1A8 , Canada.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2019 Nov 27; Vol. 62 (22), pp. 10144-10155. Date of Electronic Publication: 2019 Nov 12.
DOI: 10.1021/acs.jmedchem.9b00988
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz: