spacer SIR2 COMPLEX STRUCTURE MIXTURE OF EX-527 INHIBITOR AND REACTION PRODUCTS OR OF REACTION SUBSTRATES P53 PEPTIDE AND NAD
Primary citation
Title Ex-527 Inhibits Sirtuins by Exploiting Their Unique Nad+-Dependent Deacetylation Mechanism
Authors Gertz, M.search; Fischer, F.search; Nguyen, G.T.T.search; Lakshminarasimhan, M.search; Schutkowski, M.search; Weyand, M.search; Steegborn, C.search
Journal PROC.NATL.ACAD.SCI.USAsearch vol:110, pag:E2772 (2013), Identifiers: PubMed ID (23840057)search DOI (10.1073/pnas.1303628110)
Abstract 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.
MeSH terms
Other entries described in this publication 4bvb, 4bv2, 4bvf, 4bv3, 4bvg, 4bvh, 4bve
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