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Structural Basis of Sirtuin 6 Activation by Synthetic Small Molecules

Title data

You, Weijie ; Rotili, Dante ; Li, Tie-Mei ; Kambach, Christian ; Meleshin, Marat ; Schutkowski, Mike ; Chua, Katrin F. ; Mai, Antonello ; Steegborn, Clemens:
Structural Basis of Sirtuin 6 Activation by Synthetic Small Molecules.
In: Angewandte Chemie International Edition. Vol. 56 (19 January 2017) Issue 4 . - pp. 1007-1011.
ISSN 1521-3773
DOI: https://doi.org/10.1002/anie.201610082

Abstract in another language

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.

Further data

Item Type: Article in a journal
Refereed: Yes
Institutions of the University: Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry > Chair Biochemistry - Univ.-Prof. Dr. Clemens Steegborn
Faculties
Faculties > Faculty of Biology, Chemistry and Earth Sciences
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry
Result of work at the UBT: No
DDC Subjects: 600 Technology, medicine, applied sciences
Date Deposited: 06 Apr 2017 08:33
Last Modified: 06 Apr 2017 08:33
URI: https://eref.uni-bayreuth.de/id/eprint/36701