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| | <StructureSection load='6d4p' size='340' side='right'caption='[[6d4p]], [[Resolution|resolution]] 2.11Å' scene=''> | | <StructureSection load='6d4p' size='340' side='right'caption='[[6d4p]], [[Resolution|resolution]] 2.11Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6d4p]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6D4P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6D4P FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6d4p]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6D4P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6D4P FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">UBE2D1, SFT, UBC5A, UBCH5, UBCH5A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.11Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6d4p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d4p OCA], [http://pdbe.org/6d4p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6d4p RCSB], [http://www.ebi.ac.uk/pdbsum/6d4p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6d4p ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6d4p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d4p OCA], [https://pdbe.org/6d4p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6d4p RCSB], [https://www.ebi.ac.uk/pdbsum/6d4p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6d4p ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/UB2D1_HUMAN UB2D1_HUMAN]] Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-48'-linked polyubiquitination. Mediates the selective degradation of short-lived and abnormal proteins. Functions in the E6/E6-AP-induced ubiquitination of p53/TP53. Mediates ubiquitination of PEX5 and auto-ubiquitination of STUB1, TRAF6 and TRIM63/MURF1. Ubiquitinates STUB1-associated HSP90AB1 in vitro. Lacks inherent specificity for any particular lysine residue of ubiquitin. Essential for viral activation of IRF3. Mediates polyubiquitination of CYP3A4.<ref>PMID:18042044</ref> <ref>PMID:18359941</ref> <ref>PMID:19103148</ref> <ref>PMID:19854139</ref> <ref>PMID:20061386</ref> | + | [https://www.uniprot.org/uniprot/UB2D1_HUMAN UB2D1_HUMAN] Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-48'-linked polyubiquitination. Mediates the selective degradation of short-lived and abnormal proteins. Functions in the E6/E6-AP-induced ubiquitination of p53/TP53. Mediates ubiquitination of PEX5 and auto-ubiquitination of STUB1, TRAF6 and TRIM63/MURF1. Ubiquitinates STUB1-associated HSP90AB1 in vitro. Lacks inherent specificity for any particular lysine residue of ubiquitin. Essential for viral activation of IRF3. Mediates polyubiquitination of CYP3A4.<ref>PMID:18042044</ref> <ref>PMID:18359941</ref> <ref>PMID:19103148</ref> <ref>PMID:19854139</ref> <ref>PMID:20061386</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6d4p" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6d4p" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[3D structures of ubiquitin|3D structures of ubiquitin]] |
| | + | *[[3D structures of ubiquitin conjugating enzyme|3D structures of ubiquitin conjugating enzyme]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Ceccarelli, D F]] | + | [[Category: Ceccarelli DF]] |
| - | [[Category: Garg, P]] | + | [[Category: Garg P]] |
| - | [[Category: Sicheri, F]] | + | [[Category: Sicheri F]] |
| - | [[Category: Sidhu, S]] | + | [[Category: Sidhu S]] |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Ubiquitin]]
| + | |
| - | [[Category: Ubiquitin conjugating enzyme]]
| + | |
| - | [[Category: Ubiquitin variant]]
| + | |
| Structural highlights
Function
UB2D1_HUMAN Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-48'-linked polyubiquitination. Mediates the selective degradation of short-lived and abnormal proteins. Functions in the E6/E6-AP-induced ubiquitination of p53/TP53. Mediates ubiquitination of PEX5 and auto-ubiquitination of STUB1, TRAF6 and TRIM63/MURF1. Ubiquitinates STUB1-associated HSP90AB1 in vitro. Lacks inherent specificity for any particular lysine residue of ubiquitin. Essential for viral activation of IRF3. Mediates polyubiquitination of CYP3A4.[1] [2] [3] [4] [5]
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[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Windheim M, Peggie M, Cohen P. Two different classes of E2 ubiquitin-conjugating enzymes are required for the mono-ubiquitination of proteins and elongation by polyubiquitin chains with a specific topology. Biochem J. 2008 Feb 1;409(3):723-9. PMID:18042044 doi:10.1042/BJ20071338
- ↑ Grou CP, Carvalho AF, Pinto MP, Wiese S, Piechura H, Meyer HE, Warscheid B, Sa-Miranda C, Azevedo JE. Members of the E2D (UbcH5) family mediate the ubiquitination of the conserved cysteine of Pex5p, the peroxisomal import receptor. J Biol Chem. 2008 May 23;283(21):14190-7. doi: 10.1074/jbc.M800402200. Epub 2008 , Mar 22. PMID:18359941 doi:10.1074/jbc.M800402200
- ↑ Pabarcus MK, Hoe N, Sadeghi S, Patterson C, Wiertz E, Correia MA. CYP3A4 ubiquitination by gp78 (the tumor autocrine motility factor receptor, AMFR) and CHIP E3 ligases. Arch Biochem Biophys. 2009 Mar 1;483(1):66-74. doi: 10.1016/j.abb.2008.12.001., Epub 2008 Dec 10. PMID:19103148 doi:10.1016/j.abb.2008.12.001
- ↑ Zeng W, Xu M, Liu S, Sun L, Chen ZJ. Key role of Ubc5 and lysine-63 polyubiquitination in viral activation of IRF3. Mol Cell. 2009 Oct 23;36(2):315-25. doi: 10.1016/j.molcel.2009.09.037. PMID:19854139 doi:10.1016/j.molcel.2009.09.037
- ↑ David Y, Ziv T, Admon A, Navon A. The E2 ubiquitin conjugating enzymes direct polyubiquitination to preferred lysines. J Biol Chem. 2010 Jan 8. PMID:20061386 doi:M109.089003
- ↑ Garg P, Ceccarelli DF, Keszei AF, Kourinov I, Sicheri F, Sidhu SS. Structural and Functional Analysis of Ubiquitin-based inhibitors that Target the Backsides of E2 Enzymes. J Mol Biol. 2019 Oct 18. pii: S0022-2836(18)30280-8. doi:, 10.1016/j.jmb.2019.09.024. PMID:31634471 doi:http://dx.doi.org/10.1016/j.jmb.2019.09.024
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