4BVG: Crystal Structure Of Human Sirt3 In Complex With Native Alkylimidate Formed From Acetyl-lysine Acs2-peptide Crystallized In Presence Of The Inhibitor Ex-527

Citation:
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.
PDB ID: 4BVGDownload
MMDB ID: 111800
PDB Deposition Date: 2013/6/25
Updated in MMDB: 2013/08
Experimental Method:
x-ray diffraction
Resolution: 2.5  Å
Source Organism:
Similar Structures:
Biological Unit for 4BVG: monomeric; determined by author
Molecular Components in 4BVG
Label Count Molecule
Protein (1 molecule)
1
Nad-dependent Protein Deacetylase Sirtuin-3, Mitochondrial(Gene symbol: SIRT3)
Molecule annotation
Chemicals (15 molecules)
1
7
2
3
3
2
4
1
5
1
6
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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