5xu8
Crystal structure of human USP2 in complex with ubiquitin and 6-thioguanine
Structural highlights
FunctionUBP2_HUMAN Hydrolase that deubiquitinates polyubiquitinated target proteins such as MDM2, MDM4 and CCND1. Isoform 1 and isoform 4 possess both ubiquitin-specific peptidase and isopeptidase activities. Deubiquitinates MDM2 without reversing MDM2-mediated p53/TP53 ubiquitination and thus indirectly promotes p53/TP53 degradation and limits p53 activity. Has no deubiquitinase activity against p53/TP53. Prevents MDM2-mediated degradation of MDM4. Plays a role in the G1/S cell-cycle progression in normal and cancer cells. Plays a role in the regulation of myogenic differentiation of embryonic muscle cells.[1] [2] [3] Publication Abstract from PubMedUbiquitin-specific protease 2 (USP2) belongs to the family of deubiquitinases that can rescue protein targets from proteasomal degradation by reversing their ubiquitination. In various cancers, including prostate cancer and ovarian carcinoma, upregulation of USP2 leads to an increase in the levels of deubiquitinated substrates such as fatty acid synthase, MDM2, cyclin D1 and Aurora-A. USP2 thus plays a critical role in tumor cells' survival and therefore represents a therapeutic target. Here a leukemia drug, 6-thioguanine, was found to be a potent inhibitor of USP2. Enzyme-kinetic and X-ray crystallographic data suggest that 6-thioguanine displays a noncompetitive and slow-binding inhibitory mechanism against USP2. Our study provides a clear rationale for the clinical evaluation of 6-thioguanine for USP2-upregulated cancers. 6-Thioguanine is a noncompetitive and slow binding inhibitor of human deubiquitinating protease USP2.,Chuang SJ, Cheng SC, Tang HC, Sun CY, Chou CY Sci Rep. 2018 Feb 15;8(1):3102. doi: 10.1038/s41598-018-21476-w. PMID:29449607[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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