4BVB

CRYSTAL STRUCTURE OF HUMAN SIRT3 IN COMPLEX WITH THE INHIBITOR EX-527 AND ADP-RIBOSE

Summary for 4BVB

• Entry DOI: 10.2210/pdb4bvb/pdb
• Related: 4BUZ 4BV2 4BV3 4BVE 4BVF 4BVG 4BVH
• Descriptor: NAD-DEPENDENT PROTEIN DEACETYLASE SIRTUIN-3, MITOCHONDRIAL, (1S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1- carboxamide, [(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHYL [HYDROXY-[[(2R,3S,4R,5S)-3,4,5-TRIHYDROXYOXOLAN-2-YL]METHOXY]PHOSPHORYL] HYDROGEN PHOSPHATE, ... (5 entities in total)
• Functional Keywords: hydrolase, nad-dependent deacetylase, inhibitor complex, adp-ribose
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Mitochondrion matrix: Q9NTG7
• Total number of polymer chains: 1
• Total formula weight: 32357.65

Authors

Gertz, M.,Weyand, M.,Steegborn, C. (deposition date: 2013-06-25, release date: 2013-07-17, Last modification date: 2023-12-20)

Primary citation

Gertz, M.,Fischer, F.,Nguyen, G.T.T.,Lakshminarasimhan, M.,Schutkowski, M.,Weyand, M.,Steegborn, C.
Ex-527 Inhibits Sirtuins by Exploiting Their Unique Nad+-Dependent Deacetylation Mechanism
Proc.Natl.Acad.Sci.USA, 110:E2772-, 2013

PubMed 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.

PubMed: 23840057
DOI: 10.1073/PNAS.1303628110

Experimental method

X-RAY DIFFRACTION (2 Å)