9qje

USP7 Covalently Bound to N-(6-Fluoro-3-nitropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-amine (GCL36, 7a) with Partial Occupancy

spinqualitylabelsall models 9qje, resolution 2.26Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9qje is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.26Å Ligands: A1I71, BR, EDO, PEG 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 The cysteine protease ubiquitin-specific protease 7 (USP7), also known as herpes-associated ubiquitin-specific protease (HAUSP), has gained increasing attention in recent years due to its proven overexpression in several cancer types and its role in tumorigenesis. Herein, after a design based on molecular docking experiments, we report the synthesis of a series of mildly electrophilic compounds that covalently modify the catalytic cysteine 223 in USP7 through a nucleophilic aromatic substitution (S(N)Ar) reaction. The compounds were first evaluated using differential scanning fluorimetry (DSF) to describe their influence on the melting temperature of native and mutant USP7 variants. Furthermore, the possible formation of a covalent bond was analyzed using intact protein mass spectrometry (MS). For promising derivatives, IC(50) values were determined in an enzyme activity assay to confirm an inhibitory effect on USP7. Finally, a co-crystal structure revealed that the prototype compound (7a) arylates the catalytic cysteine in the apo form of USP7 via an unconventional binding mode near the catalytic triad. The synthesis and biological evaluation of this compound series provides valuable structure-activity relationships (SAR) and reveals an interesting and unprecedented binding mode, thus providing a basis for improving USP7 inhibitors. Design, Synthesis, and Molecular Evaluation of S(N)Ar-Reactive N-(6-Fluoro-3-Nitropyridin-2-yl)Isoquinolin-3-Amines as Covalent USP7 Inhibitors Reveals an Unconventional Binding Mode.,Ernst LN, Stahlecker J, Mier F, Serafim RAM, Wydra VR, Masberg B, Jaag SJ, Knappe C, Lammerhofer M, Stehle T, Gehringer M, Boeckler FM Arch Pharm (Weinheim). 2025 Aug;358(8):e70053. doi: 10.1002/ardp.70053. PMID:40785232 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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