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


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.

SUBMITTER: Jin L 

PROVIDER: S-EPMC2782032 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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

Jin Lei L   Wei Wentao W   Jiang Yaobin Y   Peng Hao H   Cai Jianhua J   Mao Chen C   Dai Han H   Choy Wendy W   Bemis Jean E JE   Jirousek Michael R MR   Milne Jill C JC   Westphal Christoph H CH   Perni Robert B RB  

The Journal of biological chemistry 20090616 36


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  ...[more]

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