6d68

Ube2G1 in complex with ubiquitin variant Ubv.G1.1

spinqualitylabelsall models 6d68, resolution 2.36Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6d68 is a 4 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 2.36Å Ligands: CME Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function UB2G1_HUMAN Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-48'-, as well as 'Lys-63'-linked polyubiquitination. May be involved in degradation of muscle-specific proteins. Mediates polyubiquitination of CYP3A4. Publication Abstract from PubMed Ubiquitin-conjugating E2 enzymes are central to the ubiquitination cascade and have been implicated in cancer and other diseases. Despite strong interest in developing specific E2 inhibitors, the shallow and exposed active site has proven recalcitrant to targeting with reversible small-molecule inhibitors. Here, we used phage display to generate highly potent and selective ubiquitin variants (UbVs) that target the E2 backside, which is located opposite to the active site. A UbV targeting Ube2D1 did not affect charging but greatly attenuated chain elongation. Likewise, a UbV targeting the E2 variant Ube2V1 did not interfere with the charging of its partner E2 enzyme but inhibited formation of di-ubiquitin. In contrast, a UbV that bound to the backside of Ube2G1 impeded the generation of thioester-linked ubiquitin to the active site cysteine of Ube2G1 by the E1 enzyme. Crystal structures of UbVs in complex with three E2 proteins revealed distinctive molecular interactions in each case, but they also highlighted a common backside pocket that the UbVs utilized for enhanced affinity and specificity. These findings validate the E2 backside as a target for inhibition and provide structural insights to aid inhibitor design and screening efforts. Structural and Functional Analysis of Ubiquitin-based inhibitors that Target the Backsides of E2 Enzymes.,Garg P, Ceccarelli DF, Keszei AF, Kourinov I, Sicheri F, Sidhu SS J Mol Biol. 2019 Oct 18. pii: S0022-2836(18)30280-8. doi:, 10.1016/j.jmb.2019.09.024. PMID:31634471 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also 3D structures of ubiquitin conjugating enzyme

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