Download MendeleyCrystal Structures of Human SIRT3 Displaying Substrate-induced Conformational Changes.
Jin, L., Wei, W., Jiang, Y., Peng, H., Cai, J., Mao, C., Dai, H., Choy, W., Bemis, J.E., Jirousek, M.R., Milne, J.C., Westphal, C.H., Perni, R.B.(2009) J Biol Chem 284: 24394-24405
- PubMed: 19535340
- DOI: https://doi.org/10.1074/jbc.M109.014928
- Primary Citation of Related Structures:
3GLR, 3GLS, 3GLT, 3GLU - PubMed 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.
Organizational Affiliation:
Sirtris, a GSK Company, Cambridge, Massachusetts 02139, USA. [email protected]
