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| | <StructureSection load='6cwy' size='340' side='right'caption='[[6cwy]], [[Resolution|resolution]] 2.46Å' scene=''> | | <StructureSection load='6cwy' size='340' side='right'caption='[[6cwy]], [[Resolution|resolution]] 2.46Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6cwy]] 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=6CWY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CWY FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6cwy]] 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=6CWY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CWY FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FHJ:dimethyl+(1S,2S,3R,4R)-1-[(1S)-2-(4-methylphenyl)-1-(phenylamino)ethyl]-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate'>FHJ</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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]] 2.462Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SAE1, AOS1, SUA1, UBLE1A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), UBA2, SAE2, UBLE1B, HRIHFB2115 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FHJ:dimethyl+(1S,2S,3R,4R)-1-[(1S)-2-(4-methylphenyl)-1-(phenylamino)ethyl]-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate'>FHJ</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=6cwy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cwy OCA], [http://pdbe.org/6cwy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cwy RCSB], [http://www.ebi.ac.uk/pdbsum/6cwy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cwy 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=6cwy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cwy OCA], [https://pdbe.org/6cwy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6cwy RCSB], [https://www.ebi.ac.uk/pdbsum/6cwy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6cwy ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/SAE1_HUMAN SAE1_HUMAN]] The heterodimer acts as a E1 ligase for SUMO1, SUMO2, SUMO3, and probably SUMO4. It mediates ATP-dependent activation of SUMO proteins followed by formation of a thioester bond between a SUMO protein and a conserved active site cysteine residue on UBA2/SAE2.<ref>PMID:9920803</ref> <ref>PMID:10217437</ref> <ref>PMID:10187858</ref> <ref>PMID:11481243</ref> <ref>PMID:11451954</ref> <ref>PMID:15660128</ref> <ref>PMID:20164921</ref> [[http://www.uniprot.org/uniprot/SAE2_HUMAN SAE2_HUMAN]] The heterodimer acts as a E1 ligase for SUMO1, SUMO2, SUMO3, and probably SUMO4. It mediates ATP-dependent activation of SUMO proteins followed by formation of a thioester bond between a SUMO protein and a conserved active site cysteine residue on UBA2/SAE2.<ref>PMID:11481243</ref> <ref>PMID:11451954</ref> <ref>PMID:19443651</ref> <ref>PMID:15660128</ref> <ref>PMID:17643372</ref> <ref>PMID:20164921</ref> | + | [https://www.uniprot.org/uniprot/SAE1_HUMAN SAE1_HUMAN] The heterodimer acts as a E1 ligase for SUMO1, SUMO2, SUMO3, and probably SUMO4. It mediates ATP-dependent activation of SUMO proteins followed by formation of a thioester bond between a SUMO protein and a conserved active site cysteine residue on UBA2/SAE2.<ref>PMID:9920803</ref> <ref>PMID:10217437</ref> <ref>PMID:10187858</ref> <ref>PMID:11481243</ref> <ref>PMID:11451954</ref> <ref>PMID:15660128</ref> <ref>PMID:20164921</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 6cwy" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6cwy" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[3D structures of Ubiquitin activating enzyme|3D structures of Ubiquitin activating enzyme]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Atkison, J H]] | + | [[Category: Atkison JH]] |
| - | [[Category: Lv, Z]] | + | [[Category: Lv Z]] |
| - | [[Category: Olsen, S K]] | + | [[Category: Olsen SK]] |
| - | [[Category: Williams, K M]] | + | [[Category: Williams KM]] |
| - | [[Category: Yuan, L]] | + | [[Category: Yuan L]] |
| - | [[Category: Activity]]
| + | |
| - | [[Category: Atp binding]]
| + | |
| - | [[Category: Atp/mg binding]]
| + | |
| - | [[Category: Ligase]]
| + | |
| - | [[Category: Ligase activity]]
| + | |
| - | [[Category: Rossmann-like fold]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| - | [[Category: Ubiquitin activating enzyme]]
| + | |
| - | [[Category: Ubiquitin e2]]
| + | |
| - | [[Category: Ubiquitin-like fold]]
| + | |
| Structural highlights
6cwy is a 2 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 2.462Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
SAE1_HUMAN The heterodimer acts as a E1 ligase for SUMO1, SUMO2, SUMO3, and probably SUMO4. It mediates ATP-dependent activation of SUMO proteins followed by formation of a thioester bond between a SUMO protein and a conserved active site cysteine residue on UBA2/SAE2.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
E1 enzymes activate ubiquitin (Ub) and ubiquitin-like modifiers (Ubls) in the first step of Ub/Ubl conjugation cascades and represent potential targets for therapeutic intervention in cancer and other life-threatening diseases. Here, we report the crystal structure of the E1 enzyme for the Ubl SUMO in complex with a recently discovered and highly specific covalent allosteric inhibitor (COH000). The structure reveals that COH000 targets a cryptic pocket distinct from the active site that is completely buried in all previous SUMO E1 structures and that COH000 binding to SUMO E1 is accompanied by a network of structural changes that altogether lock the enzyme in a previously unobserved inactive conformation. These structural changes include disassembly of the active site and a 180 degrees rotation of the catalytic cysteine-containing SCCH domain, relative to conformational snapshots of SUMO E1 poised to catalyze adenylation. Altogether, our study provides a molecular basis for the inhibitory mechanism of COH000 and its SUMO E1 specificity, and also establishes a framework for potential development of molecules targeting E1 enzymes for other Ubls at a cryptic allosteric site.
Molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme.,Lv Z, Yuan L, Atkison JH, Williams KM, Vega R, Sessions EH, Divlianska DB, Davies C, Chen Y, Olsen SK Nat Commun. 2018 Dec 4;9(1):5145. doi: 10.1038/s41467-018-07015-1. PMID:30514846[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Okuma T, Honda R, Ichikawa G, Tsumagari N, Yasuda H. In vitro SUMO-1 modification requires two enzymatic steps, E1 and E2. Biochem Biophys Res Commun. 1999 Jan 27;254(3):693-8. PMID:9920803 doi:10.1006/bbrc.1998.9995
- ↑ Gong L, Li B, Millas S, Yeh ET. Molecular cloning and characterization of human AOS1 and UBA2, components of the sentrin-activating enzyme complex. FEBS Lett. 1999 Apr 1;448(1):185-9. PMID:10217437
- ↑ Desterro JM, Rodriguez MS, Kemp GD, Hay RT. Identification of the enzyme required for activation of the small ubiquitin-like protein SUMO-1. J Biol Chem. 1999 Apr 9;274(15):10618-24. PMID:10187858
- ↑ Azuma Y, Tan SH, Cavenagh MM, Ainsztein AM, Saitoh H, Dasso M. Expression and regulation of the mammalian SUMO-1 E1 enzyme. FASEB J. 2001 Aug;15(10):1825-7. PMID:11481243
- ↑ Tatham MH, Jaffray E, Vaughan OA, Desterro JM, Botting CH, Naismith JH, Hay RT. Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J Biol Chem. 2001 Sep 21;276(38):35368-74. Epub 2001 Jul 12. PMID:11451954 doi:10.1074/jbc.M104214200
- ↑ Lois LM, Lima CD. Structures of the SUMO E1 provide mechanistic insights into SUMO activation and E2 recruitment to E1. EMBO J. 2005 Feb 9;24(3):439-51. Epub 2005 Jan 20. PMID:15660128
- ↑ Olsen SK, Capili AD, Lu X, Tan DS, Lima CD. Active site remodelling accompanies thioester bond formation in the SUMO E1. Nature. 2010 Feb 18;463(7283):906-12. PMID:20164921 doi:10.1038/nature08765
- ↑ Lv Z, Yuan L, Atkison JH, Williams KM, Vega R, Sessions EH, Divlianska DB, Davies C, Chen Y, Olsen SK. Molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme. Nat Commun. 2018 Dec 4;9(1):5145. doi: 10.1038/s41467-018-07015-1. PMID:30514846 doi:http://dx.doi.org/10.1038/s41467-018-07015-1
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