4BVH

CRYSTAL STRUCTURE OF HUMAN SIRT3 IN COMPLEX WITH THE INHIBITOR EX-527 AND 2'-O-ACETYL-ADP-RIBOSE

4BVH の概要

• エントリーDOI: 10.2210/pdb4bvh/pdb
• 関連するPDBエントリー: 4BUZ 4BV2 4BV3 4BVB 4BVE 4BVF 4BVG
• 分子名称: NAD-DEPENDENT PROTEIN DEACETYLASE SIRTUIN-3, MITOCHONDRIAL, (1S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1- carboxamide, 2'-O-ACETYL ADENOSINE-5-DIPHOSPHORIBOSE, ... (10 entities in total)
• 機能のキーワード: hydrolase, inhibitor complex, ex-527
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Mitochondrion matrix: Q9NTG7
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 97653.36

構造登録者

Gertz, M.,Weyand, M.,Steegborn, C. (登録日: 2013-06-25, 公開日: 2013-07-17, 最終更新日: 2023-12-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.9 Å)