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| | <StructureSection load='4c7b' size='340' side='right'caption='[[4c7b]], [[Resolution|resolution]] 2.10Å' scene=''> | | <StructureSection load='4c7b' size='340' side='right'caption='[[4c7b]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4c7b]] 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=4C7B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4C7B FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4c7b]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4C7B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4C7B FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BVB:5-[(E)-2-(4-BROMOPHENYL)ETHENYL]BENZENE-1,3-DIOL'>BVB</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</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]] 2.1Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=FDL:N~6~-ACETYL-N-(4-METHYL-2-OXO-2H-CHROMEN-7-YL)-L-LYSINAMIDE'>FDL</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BVB:5-[(E)-2-(4-BROMOPHENYL)ETHENYL]BENZENE-1,3-DIOL'>BVB</scene>, <scene name='pdbligand=FDL:N~6~-ACETYL-N-(4-METHYL-2-OXO-2H-CHROMEN-7-YL)-L-LYSINAMIDE'>FDL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4c78|4c78]]</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=4c7b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c7b OCA], [https://pdbe.org/4c7b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4c7b RCSB], [https://www.ebi.ac.uk/pdbsum/4c7b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4c7b ProSAT]</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=4c7b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c7b OCA], [http://pdbe.org/4c7b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4c7b RCSB], [http://www.ebi.ac.uk/pdbsum/4c7b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4c7b ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/SIR3_HUMAN SIR3_HUMAN]] NAD-dependent protein deacetylase. Activates mitochondrial target proteins, including ACSS1, IDH2 and GDH by deacetylating key lysine residues. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels.<ref>PMID:16788062</ref> <ref>PMID:18680753</ref> <ref>PMID:18794531</ref> <ref>PMID:19535340</ref> | + | [https://www.uniprot.org/uniprot/SIR3_HUMAN SIR3_HUMAN] NAD-dependent protein deacetylase. Activates mitochondrial target proteins, including ACSS1, IDH2 and GDH by deacetylating key lysine residues. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels.<ref>PMID:16788062</ref> <ref>PMID:18680753</ref> <ref>PMID:18794531</ref> <ref>PMID:19535340</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== |
| - | *[[Histone deacetylase|Histone deacetylase]] | + | *[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Gertz, M]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Nguyen, G T.T]] | + | [[Category: Gertz M]] |
| - | [[Category: Steegborn, C]]
| + | [[Category: Nguyen GTT]] |
| - | [[Category: Weyand, M]]
| + | [[Category: Steegborn C]] |
| - | [[Category: Activation]] | + | [[Category: Weyand M]] |
| - | [[Category: Aging]] | + | |
| - | [[Category: Hydrolase]] | + | |
| - | [[Category: Hydrolase-peptide complex]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Metabolic sensor]]
| + | |
| - | [[Category: Metabolism]]
| + | |
| - | [[Category: Resveratrol]]
| + | |
| - | [[Category: Sirt1]]
| + | |
| - | [[Category: Sirtuin]]
| + | |
| Structural highlights
4c7b is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.1Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
SIR3_HUMAN NAD-dependent protein deacetylase. Activates mitochondrial target proteins, including ACSS1, IDH2 and GDH by deacetylating key lysine residues. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels.[1] [2] [3] [4]
Publication Abstract from PubMed
Sirtuins are protein deacetylases regulating aging processes and various physiological functions. Resveratrol, a polyphenol found in red wine, activates human Sirt1 and inhibits Sirt3, and it can mimic calorie restriction effects, such as lifespan extension in lower organisms. The mechanism of Sirtuin modulation by resveratrol is not well understood. We used 4'-bromo-resveratrol (5-(2-(4-hydroxyphenyl)vinyl)-1,3-benzenediol) to study Sirt1 and Sirt3 modulation. Despite its similarity to the Sirt1 activator resveratrol, the compound potently inhibited both, Sirt1 and Sirt3. Crystal structures of Sirt3 in complex with a fluorophore-labeled and with a native substrate peptide, respectively, in presence of 4'-bromo-resveratrol reveal two compound binding sites. Biochemical studies identify the internal site and substrate competition as the mechanism for inhibition, providing a drug target site, and homology modeling suggests that the second, allosteric site might indicate the site for Sirt1 activation.
Crystal structures of sirt3 complexes with 4'-bromo-resveratrol reveal binding sites and inhibition mechanism.,Nguyen GT, Gertz M, Steegborn C Chem Biol. 2013 Nov 21;20(11):1375-85. doi: 10.1016/j.chembiol.2013.09.019. Epub , 2013 Nov 7. PMID:24211137[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Schwer B, Bunkenborg J, Verdin RO, Andersen JS, Verdin E. Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10224-9. Epub 2006 Jun 20. PMID:16788062 doi:10.1073/pnas.0603968103
- ↑ Schlicker C, Gertz M, Papatheodorou P, Kachholz B, Becker CF, Steegborn C. Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5. J Mol Biol. 2008 Oct 10;382(3):790-801. doi: 10.1016/j.jmb.2008.07.048. Epub 2008, Jul 25. PMID:18680753 doi:10.1016/j.jmb.2008.07.048
- ↑ Ahn BH, Kim HS, Song S, Lee IH, Liu J, Vassilopoulos A, Deng CX, Finkel T. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14447-52. doi:, 10.1073/pnas.0803790105. Epub 2008 Sep 15. PMID:18794531 doi:10.1073/pnas.0803790105
- ↑ Jin L, Wei W, Jiang Y, Peng H, Cai J, Mao C, Dai H, Choy W, Bemis JE, Jirousek MR, Milne JC, Westphal CH, Perni RB. Crystal structures of human SIRT3 displaying substrate-induced conformational changes. J Biol Chem. 2009 Sep 4;284(36):24394-405. Epub 2009 Jun 16. PMID:19535340 doi:10.1074/jbc.M109.014928
- ↑ Nguyen GT, Gertz M, Steegborn C. Crystal structures of sirt3 complexes with 4'-bromo-resveratrol reveal binding sites and inhibition mechanism. Chem Biol. 2013 Nov 21;20(11):1375-85. doi: 10.1016/j.chembiol.2013.09.019. Epub , 2013 Nov 7. PMID:24211137 doi:http://dx.doi.org/10.1016/j.chembiol.2013.09.019
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