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Structural Basis of Sirtuin 6 Activation by Synthetic Small Molecules
Author(s) -
You Weijie,
Rotili Dante,
Li TieMei,
Kambach Christian,
Meleshin Marat,
Schutkowski Mike,
Chua Katrin F.,
Mai Antonello,
Steegborn Clemens
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201610082
Subject(s) - sirtuin , small molecule , chemistry , activator (genetics) , acetylation , sirt2 , histone , drug discovery , biochemistry , sirt6 , chemical biology , peptide , combinatorial chemistry , enzyme , nad+ kinase , dna , gene
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.