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J Biol Chem. 2009 Sep 4;284(36):24394-405. doi: 10.1074/jbc.M109.014928. Epub 2009 Jun 16.

Crystal structures of human SIRT3 displaying substrate-induced conformational changes.

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  • 1Sirtris, a GSK Company, Cambridge, Massachusetts 02139, USA. leijin05@yahoo.com

Abstract

SIRT3 is a major mitochondrial NAD(+)-dependent protein deacetylase playing important roles in regulating mitochondrial metabolism and energy production and has been linked to the beneficial effects of exercise and caloric restriction. SIRT3 is emerging as a potential therapeutic target to treat metabolic and neurological diseases. We report the first sets of crystal structures of human SIRT3, an apo-structure with no substrate, a structure with a peptide containing acetyl lysine of its natural substrate acetyl-CoA synthetase 2, a reaction intermediate structure trapped by a thioacetyl peptide, and a structure with the dethioacetylated peptide bound. These structures provide insights into the conformational changes induced by the two substrates required for the reaction, the acetylated substrate peptide and NAD(+). In addition, the binding study by isothermal titration calorimetry suggests that the acetylated peptide is the first substrate to bind to SIRT3, before NAD(+). These structures and biophysical studies provide key insight into the structural and functional relationship of the SIRT3 deacetylation activity.

PMID:
19535340
[PubMed - indexed for MEDLINE]
PMCID:
PMC2782032
Free PMC Article
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