7MS6

Structure of USP5 zinc-finger ubiquitin binding domain co-crystallized with (2-fluoro-4-((4-phenylpiperidin-1-yl)sulfonyl)benzoyl)glycine

Summary for 7MS6

• Entry DOI: 10.2210/pdb7ms6/pdb
• Descriptor: Ubiquitin carboxyl-terminal hydrolase 5, N-[2-fluoro-4-(4-phenylpiperidine-1-sulfonyl)benzoyl]glycine, SULFATE ION, ... (6 entities in total)
• Functional Keywords: usp5, ubiquitin, usp, ubiquitin specific protease, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 14179.19

Authors

Mann, M.K.,Zepeda-Velazquez, C.A.,Alvarez, H.G.,Dong, A.,Kiyota, T.,Aman, A.,Arrowsmith, C.H.,Al-Awar, R.,Harding, R.J.,Schapira, M. (deposition date: 2021-05-10, release date: 2021-06-09, Last modification date: 2023-10-18)

Primary citation

Mann, M.K.,Zepeda-Velazquez, C.A.,Gonzalez-Alvarez, H.,Dong, A.,Kiyota, T.,Aman, A.M.,Loppnau, P.,Li, Y.,Wilson, B.,Arrowsmith, C.H.,Al-Awar, R.,Harding, R.J.,Schapira, M.
Structure-Activity Relationship of USP5 Inhibitors.
J.Med.Chem., 64:15017-15036, 2021

PubMed Abstract: USP5 is a deubiquitinase that has been implicated in a range of diseases, including cancer, but no USP5-targeting chemical probe has been reported to date. Here, we present the progression of a chemical series that occupies the C-terminal ubiquitin-binding site of a poorly characterized zinc-finger ubiquitin binding domain (ZnF-UBD) of USP5 and competitively inhibits the catalytic activity of the enzyme. Exploration of the structure-activity relationship, complemented with crystallographic characterization of the ZnF-UBD bound to multiple ligands, led to the identification of , which binds to the USP5 ZnF-UBD with a of 2.8 μM and is selective over nine proteins containing structurally similar ZnF-UBD domains. inhibits the USP5 catalytic cleavage of a di-ubiquitin substrate in an assay. This study provides a chemical and structural framework for the discovery of a chemical probe to delineate USP5 function in cells.

PubMed: 34648286
DOI: 10.1021/acs.jmedchem.1c00889

Experimental method

X-RAY DIFFRACTION (1.55 Å)