5ok6

Ubiquitin specific protease 11 USP11 - peptide F complex

spinqualitylabelsall models 5ok6, resolution 1.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5ok6 is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.3Å Ligands: AAR, EDO, GOL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function UBP11_HUMAN Protease that can remove conjugated ubiquitin from target proteins and polyubiquitin chains. Inhibits the degradation of target proteins by the proteasome. Plays a role in the regulation of pathways leading to NF-kappa-B activation. Plays a role in the regulation of DNA repair after double-stranded DNA breaks. Publication Abstract from PubMed Ubiquitin-specific proteases (USPs) reverse ubiquitination and regulate virtually all cellular processes. Defined noncatalytic domains in USP4 and USP15 are known to interact with E3 ligases and substrate recruitment factors. No such interactions have been reported for these domains in the paralog USP11, a key regulator of DNA double-strand break repair by homologous recombination. We hypothesized that USP11 domains adjacent to its protease domain harbor unique peptide-binding sites. Here, using a next-generation phage display (NGPD) strategy, combining phage display library screening with next-generation sequencing, we discovered unique USP11-interacting peptide motifs. Isothermal titration calorimetry disclosed that the highest affinity peptides (KD of approximately 10 mum) exhibit exclusive selectivity for USP11 over USP4 and USP15 in vitro Furthermore, a crystal structure of a USP11-peptide complex revealed a previously unknown binding site in USP11's noncatalytic ubiquitin-like (UBL) region. This site interacted with a helical motif and is absent in USP4 and USP15. Reporter assays using USP11-WT versus a binding pocket-deficient double mutant disclosed that this binding site modulates USP11's function in homologous recombination-mediated DNA repair. The highest affinity USP11 peptide binder fused to a cellular delivery sequence induced significant nuclear localization and cell cycle arrest in S phase, affecting the viability of different mammalian cell lines. The USP11 peptide ligands and the paralog-specific functional site in USP11 identified here provide a framework for the development of new biochemical tools and therapeutic agents. We propose that an NGPD-based strategy for identifying interacting peptides may be applied also to other cellular targets. Discovery of peptide ligands targeting a specific ubiquitin-like domain-binding site in the deubiquitinase USP11.,Spiliotopoulos A, Blokpoel Ferreras L, Densham RM, Caulton SG, Maddison BC, Morris JR, Dixon JE, Gough KC, Dreveny I J Biol Chem. 2019 Jan 11;294(2):424-436. doi: 10.1074/jbc.RA118.004469. Epub 2018, Oct 29. PMID:30373771 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Thioesterase 3D structures

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