6f5h | pdb_00006f5h

Crystal structure of USP7 in complex with a 4-hydroxypiperidine based inhibitor

spinqualitylabelsall models 6f5h, resolution 2.16Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6f5h is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CQ5, GOL, SO4 Related: 5n9r, 5n9t Activity: Ubiquitinyl hydrolase 1, with EC number 3.4.19.12 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [UBP7_HUMAN] Hydrolase that deubiquitinates target proteins such as FOXO4, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN and DAXX. Together with DAXX, prevents MDM2 self-ubiquitination and enhances the E3 ligase activity of MDM2 towards p53/TP53, thereby promoting p53/TP53 ubiquitination and proteasomal degradation. Deubiquitinates p53/TP53 and MDM2 and strongly stabilizes p53/TP53 even in the presence of excess MDM2, and also induces p53/TP53-dependent cell growth repression and apoptosis. Deubiquitination of FOXO4 in presence of hydrogen peroxide is not dependent on p53/TP53 and inhibits FOXO4-induced transcriptional activity. In association with DAXX, is involved in the deubiquitination and translocation of PTEN from the nucleus to the cytoplasm, both processes that are counteracted by PML. Involved in cell proliferation during early embryonic development. Involved in transcription-coupled nucleotide excision repair (TC-NER) in response to UV damage: recruited to DNA damage sites following interaction with KIAA1530/UVSSA and promotes deubiquitination of ERCC6, preventing UV-induced degradation of ERCC6. Contributes to the overall stabilization and trans-activation capability of the herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110 during HSV-1 infection. Involved in maintenance of DNA methylation via its interaction with UHRF1 and DNMT1: acts by mediating deubiquitination of UHRF1 and DNMT1, preventing their degradation and promoting DNA methylation by DNMT1. Exhibits a preference towards 'Lys-48'-linked Ubiquitin chains. Publication Abstract from PubMed Ubiquitin specific protease 7 (USP7, HAUSP) has become an attractive target in drug discovery due to the role it plays in modulating Mdm2 levels and consequently p53. Increasing interest in USP7 is emerging due to its potential involvement in oncogenic pathways as well as possible roles in both metabolic and immune disorders in addition to viral infections. Potent, novel, and selective inhibitors of USP7 have been developed using both rational and structure-guided design enabled by high-resolution cocrystallography. Initial hits were identified via fragment-based screening, scaffold-hopping, and hybridization exercises. Two distinct subseries are described along with associated structure-activity relationship trends, as are initial efforts aimed at developing compounds suitable for in vivo experiments. Overall, these discoveries will enable further research into the wider biological role of USP7. Identification and Structure-Guided Development of Pyrimidinone Based USP7 Inhibitors.,O'Dowd CR, Helm MD, Rountree JSS, Flasz JT, Arkoudis E, Miel H, Hewitt PR, Jordan L, Barker O, Hughes C, Rozycka E, Cassidy E, McClelland K, Odrzywol E, Page N, Feutren-Burton S, Dvorkin S, Gavory G, Harrison T ACS Med Chem Lett. 2018 Feb 21;9(3):238-243. doi: 10.1021/acsmedchemlett.7b00512., eCollection 2018 Mar 8. PMID:29541367 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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