4bvf: Difference between revisions
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==CRYSTAL STRUCTURE OF HUMAN SIRT3 IN COMPLEX WITH THIOALKYLIMIDATE FORMED FROM THIO-ACETYL-LYSINE ACS2-PEPTIDE CRYSTALLIZED IN PRESENCE OF THE INHIBITOR EX-527== | ==CRYSTAL STRUCTURE OF HUMAN SIRT3 IN COMPLEX WITH THIOALKYLIMIDATE FORMED FROM THIO-ACETYL-LYSINE ACS2-PEPTIDE CRYSTALLIZED IN PRESENCE OF THE INHIBITOR EX-527== | ||
<StructureSection load='4bvf' size='340' side='right' caption='[[4bvf]], [[Resolution|resolution]] 2.70Å' scene=''> | <StructureSection load='4bvf' size='340' side='right'caption='[[4bvf]], [[Resolution|resolution]] 2.70Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4bvf]] 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=4BVF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BVF FirstGlance]. <br> | <table><tr><td colspan='2'>[[4bvf]] 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=4BVF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BVF FirstGlance]. <br> | ||
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[[Category: Acetate--CoA ligase]] | [[Category: Acetate--CoA ligase]] | ||
[[Category: Human]] | [[Category: Human]] | ||
[[Category: Large Structures]] | |||
[[Category: Gertz, M]] | [[Category: Gertz, M]] | ||
[[Category: Steegborn, C]] | [[Category: Steegborn, C]] | ||
Revision as of 16:00, 13 March 2019
CRYSTAL STRUCTURE OF HUMAN SIRT3 IN COMPLEX WITH THIOALKYLIMIDATE FORMED FROM THIO-ACETYL-LYSINE ACS2-PEPTIDE CRYSTALLIZED IN PRESENCE OF THE INHIBITOR EX-527CRYSTAL STRUCTURE OF HUMAN SIRT3 IN COMPLEX WITH THIOALKYLIMIDATE FORMED FROM THIO-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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