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| | <StructureSection load='4x3o' size='340' side='right'caption='[[4x3o]], [[Resolution|resolution]] 1.50Å' scene=''> | | <StructureSection load='4x3o' size='340' side='right'caption='[[4x3o]], [[Resolution|resolution]] 1.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4x3o]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4X3O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4X3O FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4x3o]] 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=4X3O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4X3O FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3Y0:[[(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-BIS(OXIDANYL)OXOLAN-2-YL]METHOXY-OXIDANYL-PHOSPHORYL]+[(2R,3R,4R,5R)-3-OXIDANYL-5-SULFANYL-4-TRIDECOXY-OXOLAN-2-YL]METHYL+HYDROGEN+PHOSPHATE'>3Y0</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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]] 1.5Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[4x3p|4x3p]]</div></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3Y0:[[(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-BIS(OXIDANYL)OXOLAN-2-YL]METHOXY-OXIDANYL-PHOSPHORYL]+[(2R,3R,4R,5R)-3-OXIDANYL-5-SULFANYL-4-TRIDECOXY-OXOLAN-2-YL]METHYL+HYDROGEN+PHOSPHATE'>3Y0</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SIRT2, SIR2L, SIR2L2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4x3o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x3o OCA], [https://pdbe.org/4x3o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4x3o RCSB], [https://www.ebi.ac.uk/pdbsum/4x3o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4x3o 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=4x3o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x3o OCA], [https://pdbe.org/4x3o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4x3o RCSB], [https://www.ebi.ac.uk/pdbsum/4x3o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4x3o ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/SIR2_HUMAN SIR2_HUMAN]] NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and non-histone proteins. Deacetylates 'Lys-40' of alpha-tubulin. Involved in the control of mitotic exit in the cell cycle, probably via its role in the regulation of cytoskeleton. Deacetylates PCK1, opposing proteasomal degradation. Deacetylates 'Lys-310' of RELA.<ref>PMID:12620231</ref> <ref>PMID:12697818</ref> <ref>PMID:21081649</ref> <ref>PMID:21726808</ref>
| + | [https://www.uniprot.org/uniprot/SIR2_HUMAN SIR2_HUMAN] NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and non-histone proteins. Deacetylates 'Lys-40' of alpha-tubulin. Involved in the control of mitotic exit in the cell cycle, probably via its role in the regulation of cytoskeleton. Deacetylates PCK1, opposing proteasomal degradation. Deacetylates 'Lys-310' of RELA.<ref>PMID:12620231</ref> <ref>PMID:12697818</ref> <ref>PMID:21081649</ref> <ref>PMID:21726808</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Hao, Q]] | + | [[Category: Hao Q]] |
| - | [[Category: Wang, Y]] | + | [[Category: Wang Y]] |
| - | [[Category: Zhang, W Z]] | + | [[Category: Zhang WZ]] |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Hydrolase-peptide complex]]
| + | |
| - | [[Category: Myristoyl peptide]]
| + | |
| - | [[Category: Sirt2]]
| + | |
| Structural highlights
Function
SIR2_HUMAN NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and non-histone proteins. Deacetylates 'Lys-40' of alpha-tubulin. Involved in the control of mitotic exit in the cell cycle, probably via its role in the regulation of cytoskeleton. Deacetylates PCK1, opposing proteasomal degradation. Deacetylates 'Lys-310' of RELA.[1] [2] [3] [4]
Publication Abstract from PubMed
Sirtuins are NAD-dependent deacylases. Previous studies have established two important enzymatic intermediates in sirtuin-catalyzed deacylation, an alkylamidate intermediate I, which is then converted to a bicyclic intermediate II. However, how intermediate II is converted to products is unknown. Based on potent SIRT2-specific inhibitors we developed, here we report crystal structures of SIRT2 in complexes with a thiomyristoyl lysine peptide-based inhibitor and carba-NAD or NAD. Interestingly, by soaking crystals with NAD, we capture a distinct covalent catalytic intermediate (III) that is different from the previously established intermediates I and II. In this intermediate, the covalent bond between the S and the myristoyl carbonyl carbon is broken, and we believe this intermediate III to be the decomposition product of II en route to form the end products. MALDI-TOF data further support the intermediate III formation. This is the first time such an intermediate has been captured by X-ray crystallography and provides more mechanistic insights into sirtuin-catalyzed reactions.
Deacylation Mechanism by SIRT2 Revealed in the 1'-SH-2'-O-Myristoyl Intermediate Structure.,Wang Y, Fung YME, Zhang W, He B, Chung MWH, Jin J, Hu J, Lin H, Hao Q Cell Chem Biol. 2017 Mar 16;24(3):339-345. doi: 10.1016/j.chembiol.2017.02.007., Epub 2017 Mar 9. PMID:28286128[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ North BJ, Marshall BL, Borra MT, Denu JM, Verdin E. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell. 2003 Feb;11(2):437-44. PMID:12620231
- ↑ Dryden SC, Nahhas FA, Nowak JE, Goustin AS, Tainsky MA. Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol Cell Biol. 2003 May;23(9):3173-85. PMID:12697818
- ↑ Rothgiesser KM, Erener S, Waibel S, Luscher B, Hottiger MO. SIRT2 regulates NF-kappaB dependent gene expression through deacetylation of p65 Lys310. J Cell Sci. 2010 Dec 15;123(Pt 24):4251-8. doi: 10.1242/jcs.073783. Epub 2010 Nov, 16. PMID:21081649 doi:10.1242/jcs.073783
- ↑ Jiang W, Wang S, Xiao M, Lin Y, Zhou L, Lei Q, Xiong Y, Guan KL, Zhao S. Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase. Mol Cell. 2011 Jul 8;43(1):33-44. doi: 10.1016/j.molcel.2011.04.028. PMID:21726808 doi:10.1016/j.molcel.2011.04.028
- ↑ Wang Y, Fung YME, Zhang W, He B, Chung MWH, Jin J, Hu J, Lin H, Hao Q. Deacylation Mechanism by SIRT2 Revealed in the 1'-SH-2'-O-Myristoyl Intermediate Structure. Cell Chem Biol. 2017 Mar 16;24(3):339-345. doi: 10.1016/j.chembiol.2017.02.007., Epub 2017 Mar 9. PMID:28286128 doi:http://dx.doi.org/10.1016/j.chembiol.2017.02.007
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