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4bvb

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<StructureSection load='4bvb' size='340' side='right'caption='[[4bvb]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
<StructureSection load='4bvb' size='340' side='right'caption='[[4bvb]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4bvb]] is a 1 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=4BVB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BVB FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4bvb]] is a 1 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=4BVB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BVB FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AR6:[(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHYL+[HYDROXY-[[(2R,3S,4R,5S)-3,4,5-TRIHYDROXYOXOLAN-2-YL]METHOXY]PHOSPHORYL]+HYDROGEN+PHOSPHATE'>AR6</scene>, <scene name='pdbligand=OCZ:(1S)-6-CHLORO-2,3,4,9-TETRAHYDRO-1H-CARBAZOLE-1-+CARBOXAMIDE'>OCZ</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AR6:[(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHYL+[HYDROXY-[[(2R,3S,4R,5S)-3,4,5-TRIHYDROXYOXOLAN-2-YL]METHOXY]PHOSPHORYL]+HYDROGEN+PHOSPHATE'>AR6</scene>, <scene name='pdbligand=OCZ:(1S)-6-CHLORO-2,3,4,9-TETRAHYDRO-1H-CARBAZOLE-1-+CARBOXAMIDE'>OCZ</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4bv2|4bv2]], [[4bv3|4bv3]], [[4bve|4bve]], [[4bvf|4bvf]], [[4bvg|4bvg]], [[4bvh|4bvh]], [[4buz|4buz]]</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4bvb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bvb OCA], [https://pdbe.org/4bvb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bvb RCSB], [https://www.ebi.ac.uk/pdbsum/4bvb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bvb ProSAT]</span></td></tr>
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<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=4bvb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bvb OCA], [http://pdbe.org/4bvb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4bvb RCSB], [http://www.ebi.ac.uk/pdbsum/4bvb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4bvb ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[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>
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[[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Sirtuins are protein deacetylases regulating metabolism and stress responses. The seven human Sirtuins (Sirt1-7) are attractive drug targets, but Sirtuin inhibition mechanisms are mostly unidentified. We report the molecular mechanism of Sirtuin inhibition by 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (Ex-527). Inhibitor binding to potently inhibited Sirt1 and Thermotoga maritima Sir2 and to moderately inhibited Sirt3 requires NAD+, alone or together with acetylpeptide. Crystal structures of several Sirtuin inhibitor complexes show that Ex-527 occupies the nicotinamide site and a neighboring pocket and contacts the ribose of NAD+ or of the coproduct 2'-O-acetyl-ADP ribose. Complex structures with native alkylimidate and thio-analog support its catalytic relevance and show, together with biochemical assays, that only the coproduct complex is relevant for inhibition by Ex-527, which stabilizes the closed enzyme conformation preventing product release. Ex-527 inhibition thus exploits Sirtuin catalysis, and kinetic isoform differences explain its selectivity. Our results provide insights in Sirtuin catalysis and inhibition with important implications for drug development.
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Ex-527 inhibits Sirtuins by exploiting their unique NAD+-dependent deacetylation mechanism.,Gertz M, Fischer F, Nguyen GT, Lakshminarasimhan M, Schutkowski M, Weyand M, Steegborn C Proc Natl Acad Sci U S A. 2013 Jul 9. PMID:23840057<ref>PMID:23840057</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4bvb" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Histone deacetylase|Histone deacetylase]]
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*[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Gertz, M]]
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[[Category: Gertz M]]
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[[Category: Steegborn, C]]
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[[Category: Steegborn C]]
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[[Category: Weyand, M]]
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[[Category: Weyand M]]
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[[Category: Adp-ribose]]
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[[Category: Hydrolase]]
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[[Category: Inhibitor complex]]
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[[Category: Nad-dependent deacetylase]]
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Revision as of 17:10, 7 September 2022

CRYSTAL STRUCTURE OF HUMAN SIRT3 IN COMPLEX WITH THE INHIBITOR EX-527 AND ADP-RIBOSE

PDB ID 4bvb

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