6DXT

Structure of USP5 zinc-finger ubiquitin binding domain co-crystallized with 3-(5-phenyl-1,3,4-oxadiazol-2-yl)propanoate

Summary for 6DXT

• Entry DOI: 10.2210/pdb6dxt/pdb
• Descriptor: Ubiquitin carboxyl-terminal hydrolase 5, 3-(5-phenyl-1,3,4-oxadiazol-2-yl)propanoic acid, UNKNOWN ATOM OR ION, ... (6 entities in total)
• Functional Keywords: deubiquitinase, usp5, ubiquitin, structural genomics consortium, sgc, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 27667.70

Authors

Mann, M.K.,Harding, R.J.,Ravichandran, M.,Ferreira de Freitas, R.,Franzoni, I.,Bountra, C.,Edwards, A.M.,Arrowsmith, C.M.,Schapira, M.,Structural Genomics Consortium (SGC) (deposition date: 2018-06-29, release date: 2018-08-08, Last modification date: 2024-10-16)

Primary citation

Mann, M.K.,Franzoni, I.,de Freitas, R.F.,Tempel, W.,Houliston, S.,Smith, L.,Vedadi, M.,Arrowsmith, C.H.,Harding, R.J.,Schapira, M.
Discovery of Small Molecule Antagonists of the USP5 Zinc Finger Ubiquitin-Binding Domain.
J.Med.Chem., 62:10144-10155, 2019

PubMed Abstract: 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.

PubMed: 31663737
DOI: 10.1021/acs.jmedchem.9b00988

Experimental method

X-RAY DIFFRACTION (1.95 Å)