Crystal Structures of Human SIRT3 Displaying Substrate-induced Conformational Changes

• DOI: 10.1074/jbc.m109.014928
• Publication Date: 2009-06-18T00:17:56Z
• Authors: Lei Jin; Wentao Wei; Yaobin Jiang; Hao Peng; Jianhua Cai; Chen Mao; Han Dai; Wendy Choy; Jean E. Bemis; Michael R. Jirousek; Jill C. Milne; Christoph H. West...; Robert B. Perni
• Keywords: SIRT3; Isothermal Titration Calorimetry

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