4bvg: Difference between revisions
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==CRYSTAL STRUCTURE OF HUMAN SIRT3 IN COMPLEX WITH NATIVE ALKYLIMIDATE FORMED FROM ACETYL-LYSINE ACS2-PEPTIDE CRYSTALLIZED IN PRESENCE OF THE INHIBITOR EX-527== | ==CRYSTAL STRUCTURE OF HUMAN SIRT3 IN COMPLEX WITH NATIVE ALKYLIMIDATE FORMED FROM ACETYL-LYSINE ACS2-PEPTIDE CRYSTALLIZED IN PRESENCE OF THE INHIBITOR EX-527== | ||
<StructureSection load='4bvg' size='340' side='right' caption='[[4bvg]], [[Resolution|resolution]] 2.50Å' scene=''> | <StructureSection load='4bvg' size='340' side='right' caption='[[4bvg]], [[Resolution|resolution]] 2.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4bvg]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[4bvg]] 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=4BVG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BVG FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=OAD:2-O-ACETYL+ADENOSINE-5-DIPHOSPHORIBOSE'>OAD</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=OAD:2-O-ACETYL+ADENOSINE-5-DIPHOSPHORIBOSE'>OAD</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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">[[4bv2|4bv2]], [[4bv3|4bv3]], [[4bvb|4bvb]], [[4bve|4bve]], [[4bvf|4bvf]], [[4bvh|4bvh]], [[4buz|4buz]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4bv2|4bv2]], [[4bv3|4bv3]], [[4bvb|4bvb]], [[4bve|4bve]], [[4bvf|4bvf]], [[4bvh|4bvh]], [[4buz|4buz]]</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Acetate--CoA_ligase Acetate--CoA ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.2.1.1 6.2.1.1] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Acetate--CoA_ligase Acetate--CoA ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.2.1.1 6.2.1.1] </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=4bvg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bvg OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bvg RCSB], [http://www.ebi.ac.uk/pdbsum/4bvg PDBsum]</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=4bvg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bvg OCA], [http://pdbe.org/4bvg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4bvg RCSB], [http://www.ebi.ac.uk/pdbsum/4bvg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4bvg ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 4bvg" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Histone deacetylase|Histone deacetylase]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Acetate--CoA ligase]] | [[Category: Acetate--CoA ligase]] | ||
[[Category: | [[Category: Human]] | ||
[[Category: Gertz, M]] | [[Category: Gertz, M]] | ||
[[Category: Nguyen, G T.T]] | [[Category: Nguyen, G T.T]] | ||
Revision as of 23:49, 5 August 2016
CRYSTAL STRUCTURE OF HUMAN SIRT3 IN COMPLEX WITH NATIVE ALKYLIMIDATE FORMED FROM ACETYL-LYSINE ACS2-PEPTIDE CRYSTALLIZED IN PRESENCE OF THE INHIBITOR EX-527CRYSTAL STRUCTURE OF HUMAN SIRT3 IN COMPLEX WITH NATIVE ALKYLIMIDATE FORMED FROM ACETYL-LYSINE ACS2-PEPTIDE CRYSTALLIZED IN PRESENCE OF THE INHIBITOR EX-527
Structural highlights
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] [ACS2L_HUMAN] Important for maintaining normal body temperature during fasting and for energy homeostasis. Essential for energy expenditure under ketogenic conditions (By similarity). Converts acetate to acetyl-CoA so that it can be used for oxidation through the tricarboxylic cycle to produce ATP and CO(2).[5] Publication Abstract from PubMedSirtuins 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. 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[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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