| http://purl.uniprot.org/citations/23840057 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/23840057 | http://www.w3.org/2000/01/rdf-schema#comment | "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."xsd:string |
| http://purl.uniprot.org/citations/23840057 | http://purl.org/dc/terms/identifier | "doi:10.1073/pnas.1303628110"xsd:string |
| http://purl.uniprot.org/citations/23840057 | http://purl.uniprot.org/core/author | "Weyand M."xsd:string |
| http://purl.uniprot.org/citations/23840057 | http://purl.uniprot.org/core/author | "Steegborn C."xsd:string |
| http://purl.uniprot.org/citations/23840057 | http://purl.uniprot.org/core/author | "Fischer F."xsd:string |
| http://purl.uniprot.org/citations/23840057 | http://purl.uniprot.org/core/author | "Lakshminarasimhan M."xsd:string |
| http://purl.uniprot.org/citations/23840057 | http://purl.uniprot.org/core/author | "Schutkowski M."xsd:string |
| http://purl.uniprot.org/citations/23840057 | http://purl.uniprot.org/core/author | "Nguyen G.T."xsd:string |
| http://purl.uniprot.org/citations/23840057 | http://purl.uniprot.org/core/author | "Gertz M."xsd:string |
| http://purl.uniprot.org/citations/23840057 | http://purl.uniprot.org/core/date | "2013"xsd:gYear |
| http://purl.uniprot.org/citations/23840057 | http://purl.uniprot.org/core/name | "Proc Natl Acad Sci U S A"xsd:string |
| http://purl.uniprot.org/citations/23840057 | http://purl.uniprot.org/core/pages | "E2772-81"xsd:string |
| http://purl.uniprot.org/citations/23840057 | http://purl.uniprot.org/core/title | "Ex-527 inhibits Sirtuins by exploiting their unique NAD+-dependent deacetylation mechanism."xsd:string |
| http://purl.uniprot.org/citations/23840057 | http://purl.uniprot.org/core/volume | "110"xsd:string |
| http://purl.uniprot.org/citations/23840057 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/23840057 |
| http://purl.uniprot.org/citations/23840057 | http://xmlns.com/foaf/0.1/primaryTopicOf | https://pubmed.ncbi.nlm.nih.gov/23840057 |
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