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| | ==Crystal structure of human Mms2/Ubc13 - BAY 11-7082== | | ==Crystal structure of human Mms2/Ubc13 - BAY 11-7082== |
| - | <StructureSection load='4onn' size='340' side='right' caption='[[4onn]], [[Resolution|resolution]] 1.50Å' scene=''> | + | <StructureSection load='4onn' size='340' side='right'caption='[[4onn]], [[Resolution|resolution]] 1.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4onn]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ONN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ONN FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4onn]] 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=4ONN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ONN FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BY1:3-[(4-METHYLPHENYL)SULFONYL]PROP-2-ENENITRILE'>BY1</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BY1:3-[(4-METHYLPHENYL)SULFONYL]PROP-2-ENENITRILE'>BY1</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4onl|4onl]], [[4onm|4onm]]</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=4onn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4onn OCA], [https://pdbe.org/4onn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4onn RCSB], [https://www.ebi.ac.uk/pdbsum/4onn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4onn ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Ubiquitin--protein_ligase Ubiquitin--protein ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.2.19 6.3.2.19] </span></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=4onn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4onn OCA], [http://pdbe.org/4onn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4onn RCSB], [http://www.ebi.ac.uk/pdbsum/4onn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4onn ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/UB2V2_HUMAN UB2V2_HUMAN]] Has no ubiquitin ligase activity on its own. The UBE2V2/UBE2N heterodimer catalyzes the synthesis of non-canonical poly-ubiquitin chains that are linked through 'Lys-63'. This type of poly-ubiquitination does not lead to protein degradation by the proteasome. 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.<ref>PMID:9705497</ref> <ref>PMID:10089880</ref> <ref>PMID:14562038</ref> <ref>PMID:20061386</ref> [[http://www.uniprot.org/uniprot/UBE2N_HUMAN UBE2N_HUMAN]] The UBE2V1-UBE2N and UBE2V2-UBE2N heterodimers catalyze the synthesis of non-canonical 'Lys-63'-linked polyubiquitin chains. This type of polyubiquitination does not lead to protein degradation by the proteasome. 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. Acts together with the E3 ligases, HLTF and SHPRH, in the 'Lys-63'-linked poly-ubiquitination of PCNA upon genotoxic stress, which is required for DNA repair. Appears to act together with E3 ligase RNF5 in the 'Lys-63'-linked polyubiquitination of JKAMP thereby regulating JKAMP function by decreasing its association with components of the proteasome and ERAD. 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 (By similarity).<ref>PMID:10089880</ref> <ref>PMID:14562038</ref> <ref>PMID:19269966</ref> <ref>PMID:20061386</ref> <ref>PMID:21512573</ref> | + | [https://www.uniprot.org/uniprot/UB2V2_HUMAN UB2V2_HUMAN] Has no ubiquitin ligase activity on its own. The UBE2V2/UBE2N heterodimer catalyzes the synthesis of non-canonical poly-ubiquitin chains that are linked through 'Lys-63'. This type of poly-ubiquitination does not lead to protein degradation by the proteasome. 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.<ref>PMID:9705497</ref> <ref>PMID:10089880</ref> <ref>PMID:14562038</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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| | ==See Also== | | ==See Also== |
| - | *[[Ubiquitin conjugating enzyme|Ubiquitin conjugating enzyme]] | + | *[[3D structures of ubiquitin conjugating enzyme|3D structures of ubiquitin conjugating enzyme]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Ubiquitin--protein ligase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Edwards, R A]] | + | [[Category: Large Structures]] |
| - | [[Category: Glover, J N.M]] | + | [[Category: Edwards RA]] |
| - | [[Category: Hodge, C D]] | + | [[Category: Glover JNM]] |
| - | [[Category: Covalent adduct]] | + | [[Category: Hodge CD]] |
| - | [[Category: E1]]
| + | |
| - | [[Category: E2 ubiquitin conjugating enzyme]]
| + | |
| - | [[Category: E3]]
| + | |
| - | [[Category: Ligase]]
| + | |
| - | [[Category: Ubiquitin]]
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| Structural highlights
Function
UB2V2_HUMAN Has no ubiquitin ligase activity on its own. The UBE2V2/UBE2N heterodimer catalyzes the synthesis of non-canonical poly-ubiquitin chains that are linked through 'Lys-63'. This type of poly-ubiquitination does not lead to protein degradation by the proteasome. 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.[1] [2] [3] [4]
Publication Abstract from PubMed
Ubc13 is an E2 ubiquitin conjugating enzyme that functions in nuclear DNA damage signaling and cytoplasmic NF-kappaB signaling. Here, we present the structures of complexes of Ubc13 with two inhibitors, NSC697923 and BAY 11-7082, which inhibit DNA damage and NF-kappaB signaling in human cells. NSC697923 and BAY 11-7082 both inhibit Ubc13 by covalent adduct formation through a Michael addition at the Ubc13 active site cysteine. The resulting adducts of both compounds exploit a binding groove unique to Ubc13. We developed a Ubc13 mutant which resists NSC697923 inhibition and, using this mutant, we show that the inhibition of cellular DNA damage and NF-kappaB signaling by NSC697923 is largely due to specific Ubc13 inhibition. We propose that unique structural features near the Ubc13 active site could provide a basis for the rational development and design of specific Ubc13 inhibitors.
Covalent Inhibition of Ubc13 Affects Ubiquitin Signaling and Reveals Active Site Elements Important for Targeting.,Hodge CD, Edwards RA, Markin CJ, McDonald D, Pulvino M, Huen MS, Zhao J, Spyracopoulos L, Hendzel MJ, Glover JN ACS Chem Biol. 2015 May 1. PMID:25909880[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Xiao W, Lin SL, Broomfield S, Chow BL, Wei YF. The products of the yeast MMS2 and two human homologs (hMMS2 and CROC-1) define a structurally and functionally conserved Ubc-like protein family. Nucleic Acids Res. 1998 Sep 1;26(17):3908-14. PMID:9705497
- ↑ Hofmann RM, Pickart CM. Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair. Cell. 1999 Mar 5;96(5):645-53. PMID:10089880
- ↑ Bothos J, Summers MK, Venere M, Scolnick DM, Halazonetis TD. The Chfr mitotic checkpoint protein functions with Ubc13-Mms2 to form Lys63-linked polyubiquitin chains. Oncogene. 2003 Oct 16;22(46):7101-7. PMID:14562038 doi:10.1038/sj.onc.1206831
- ↑ 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
- ↑ Hodge CD, Edwards RA, Markin CJ, McDonald D, Pulvino M, Huen MS, Zhao J, Spyracopoulos L, Hendzel MJ, Glover JN. Covalent Inhibition of Ubc13 Affects Ubiquitin Signaling and Reveals Active Site Elements Important for Targeting. ACS Chem Biol. 2015 May 1. PMID:25909880 doi:http://dx.doi.org/10.1021/acschembio.5b00222
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