6d6i
Ube2V1 in complex with ubiquitin variant Ubv.V1.1 and Ube2N/Ubc13
Structural highlights
FunctionUB2V1_HUMAN Has no ubiquitin ligase activity on its own. The UBE2V1-UBE2N heterodimer catalyzes the synthesis of non-canonical poly-ubiquitin chains that are linked through Lys-63. This type of poly-ubiquitination activates IKK and does not seem to involve protein degradation by the proteasome. Plays a role in the activation of NF-kappa-B mediated by IL1B, TNF, TRAF6 and TRAF2. Mediates transcriptional activation of target genes. Plays a role in the control of progress through the cell cycle and differentiation. Plays a role in the error-free DNA repair pathway and contributes to the survival of cells after DNA damage. Promotes TRIM5 capsid-specific restriction activity and the UBE2V1-UBE2N heterodimer acts in concert with TRIM5 to generate 'Lys-63'-linked polyubiquitin chains which activate the MAP3K7/TAK1 complex which in turn results in the induction and expression of NF-kappa-B and MAPK-responsive inflammatory genes.[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedUbiquitin-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[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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