5MGN

Human Sirt6 in complex with activator UBCS38

5MGN の概要

• エントリーDOI: 10.2210/pdb5mgn/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: 4-(pyridin-3-yl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-4, 5-dihydropyrrolo[1, 2-a]quinoxaline, drug, hydrolase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus, nucleoplasm : Q8N6T7
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 69956.79

構造登録者

Steegborn, C.,You, W.,Kambach, C. (登録日: 2016-11-21, 公開日: 2016-12-28, 最終更新日: 2024-01-17)

主引用文献

You, W.,Rotili, D.,Li, T.M.,Kambach, C.,Meleshin, M.,Schutkowski, M.,Chua, K.F.,Mai, A.,Steegborn, C.
Structural Basis of Sirtuin 6 Activation by Synthetic Small Molecules.
Angew. Chem. Int. Ed. Engl., 56:1007-1011, 2017

PubMed Abstract: Sirtuins are protein deacylases regulating metabolism and stress responses, and are implicated in aging-related diseases. Small molecule activators for the human sirtuins Sirt1-7 are sought as chemical tools and potential therapeutics, such as for cancer. Activators are available for Sirt1 and exploit its unique N-terminus, whereas drug-like activators for Sirt2-7 are lacking. We synthesized and screened pyrrolo[1,2-a]quinoxaline derivatives, yielding the first synthetic Sirt6 activators. Biochemical assays show direct, substrate-independent compound binding to the Sirt6 catalytic core and potent activation of Sirt6-dependent deacetylation of peptide substrates and complete nucleosomes. Crystal structures of Sirt6/activator complexes reveal that the compounds bind to a Sirt6-specific acyl channel pocket and identify key interactions. Our results establish potent Sirt6 activation with small molecules and provide a structural basis for further development of Sirt6 activators as tools and therapeutics.

PubMed: 27990725
DOI: 10.1002/anie.201610082

実験手法

X-RAY DIFFRACTION (2.07 Å)