6QCE

Human Sirt6 in complex with ADP-ribose and the activator isoquercetin

6QCE の概要

• エントリーDOI: 10.2210/pdb6qce/pdb
• 分子名称: NAD-dependent protein deacetylase sirtuin-6, [(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, ZINC ION, ... (7 entities in total)
• 機能のキーワード: deacylase, activator, quercetin derivative, allosteric, isoform-selective, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 70554.23

構造登録者

You, W.,Steegborn, C. (登録日: 2018-12-27, 公開日: 2019-12-25, 最終更新日: 2024-01-24)

主引用文献

You, W.,Zheng, W.,Weiss, S.,Chua, K.F.,Steegborn, C.
Structural basis for the activation and inhibition of Sirtuin 6 by quercetin and its derivatives.
Sci Rep, 9:19176-19176, 2019

PubMed Abstract: Mammalian Sirtuin 6 (Sirt6) is an NAD-dependent protein deacylase regulating metabolism and chromatin homeostasis. Sirt6 activation protects against metabolic and aging-related diseases, and Sirt6 inhibition is considered a cancer therapy. Available Sirt6 modulators show insufficient potency and specificity, and even partially contradictory Sirt6 effects were reported for the plant flavone quercetin. To understand Sirt6 modulation by quercetin-based compounds, we analysed their binding and activity effects on Sirt6 and other Sirtuin isoforms and solved crystal structures of compound complexes with Sirt6 and Sirt2. We find that quercetin activates Sirt6 via the isoform-specific binding site for pyrrolo[1,2-a]quinoxalines. Its inhibitory effect on other isoforms is based on an alternative binding site at the active site entrance. Based on these insights, we identified isoquercetin as a ligand that can discriminate both sites and thus activates Sirt6 with increased specificity. Furthermore, we find that quercetin derivatives that inhibit rather than activate Sirt6 exploit the same general Sirt6 binding site as the activators, identifying it as a versatile allosteric site for Sirt6 modulation. Our results thus provide a structural basis for Sirtuin effects of quercetin-related compounds and helpful insights for Sirt6-targeted drug development.

PubMed: 31844103
DOI: 10.1038/s41598-019-55654-1

実験手法

X-RAY DIFFRACTION (1.9 Å)