4BV2
CRYSTAL STRUCTURE OF SIR2 IN COMPLEX WITH THE INHIBITOR EX-527, 2'-O-ACETYL-ADP-RIBOSE AND DEACETYLATED P53-PEPTIDE
Summary for 4BV2
| Entry DOI | 10.2210/pdb4bv2/pdb |
| Related | 4BUZ 4BV3 4BVB 4BVE 4BVF 4BVG 4BVH |
| Descriptor | NAD-DEPENDENT PROTEIN DEACETYLASE, CELLULAR TUMOR ANTIGEN P53, ZINC ION, ... (5 entities in total) |
| Functional Keywords | hydrolase, nad-dependent deacetylase, sirtuin, inhibitor complex, ex-527, acetylated adp-ribose, hydrolase-hydrolase |
| Biological source | THERMOTOGA MARITIMA More |
| Cellular location | Cytoplasm (By similarity): Q9WYW0 Cytoplasm. Isoform 1: Nucleus. Isoform 2: Nucleus. Isoform 3: Nucleus. Isoform 4: Nucleus. Isoform 7: Nucleus. Isoform 8: Nucleus. Isoform 9: Cytoplasm: P04637 |
| Total number of polymer chains | 4 |
| Total formula weight | 60166.32 |
| Authors | Gertz, M.,Weyand, M.,Steegborn, C. (deposition date: 2013-06-24, 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 Cited by 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: 23840057DOI: 10.1073/PNAS.1303628110 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.3 Å) |
Structure validation
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