6NFT

Structure of USP5 zinc-finger ubiquitin binding domain co-crystallized with (4-oxoquinazolin-3(4H)-yl)acetic acid

Summary for 6NFT

• Entry DOI: 10.2210/pdb6nft/pdb
• Related: 6DXH 6DXT
• Descriptor: Ubiquitin carboxyl-terminal hydrolase 5, ZINC ION, (4-oxoquinazolin-3(4H)-yl)acetic acid, ... (6 entities in total)
• Functional Keywords: usp5, structural genomics, structural genomics consortium, sgc, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 27795.78

Authors

Harding, R.J.,Mann, M.K.,Tempel, W.,Bountra, C.,Arrowmsmith, C.M.,Edwards, A.M.,Schapira, M.,Structural Genomics Consortium (SGC) (deposition date: 2018-12-20, release date: 2019-01-02, 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 (1.65 Å)