5MF6

Human Sirt6 in complex with activator UBCS039

Summary for 5MF6

• Entry DOI: 10.2210/pdb5mf6/pdb
• Descriptor: 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, ... (8 entities in total)
• Functional Keywords: 4-(pyridin-3-yl)-4, 5-dihydropyrrolo[1, 2-a]quinoxaline, dihydropyrrol, drug, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus, nucleoplasm : Q8N6T7
• Total number of polymer chains: 2
• Total formula weight: 70112.11

Authors

Steegborn, C.,You, W.,Kambach, C. (deposition date: 2016-11-17, release date: 2016-12-28, Last modification date: 2024-01-17)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.87 Å)