4bv3: Difference between revisions
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==CRYSTAL STRUCTURE OF SIRT3 IN COMPLEX WITH THE INHIBITOR EX-527 AND NAD== | |||
<StructureSection load='4bv3' size='340' side='right' caption='[[4bv3]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4bv3]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BV3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BV3 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=APR:ADENOSINE-5-DIPHOSPHORIBOSE'>APR</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</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> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4bv2|4bv2]], [[4buz|4buz]], [[4bvb|4bvb]], [[4bve|4bve]], [[4bvf|4bvf]], [[4bvg|4bvg]], [[4bvh|4bvh]]</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=4bv3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bv3 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bv3 RCSB], [http://www.ebi.ac.uk/pdbsum/4bv3 PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
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> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
== | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Gertz, M | [[Category: Gertz, M]] | ||
[[Category: Nguyen, N T.T | [[Category: Nguyen, N T.T]] | ||
[[Category: Steegborn, C | [[Category: Steegborn, C]] | ||
[[Category: Weyand, M | [[Category: Weyand, M]] | ||
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
[[Category: Inhibitor]] | [[Category: Inhibitor]] | ||
Revision as of 10:01, 21 December 2014
CRYSTAL STRUCTURE OF SIRT3 IN COMPLEX WITH THE INHIBITOR EX-527 AND NAD
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