@article{52346,
  author = {J. L. Avalos and J. D. Boeke and C. Wolberger},
  title = {Structural basis for the mechanism and regulation of Sir2 enzymes},
  abstract = {<p>Sir2 proteins form a family of NAD(+)-dependent protein deacetylases required for diverse biological processes, including transcriptional silencing, suppression of rDNA recombination, control of p53 activity, regulation of acetyl-CoA synthetase, and aging. Although structures of Sir2 enzymes in the presence and absence of peptide substrate or NAD(+) have been determined, the role of the enzyme in the mechanism of cleacetylation and NAD(+) cleavage is still unclear. Here, we present additional structures of Sir2Af2 in several differently complexed states: in a productive complex with NAD(+), in a nonproductive NAD(+) complex with bound ADP-ribose, and in the unliganded state. We observe a new mode of NAD(+) binding that seems to depend on acetyl-lysine binding, in which the nicotinamide ring of NAD(+) is buried in the highly conserved "C" pocket of the enzyme. We propose a detailed structure-based mechanism for cleacetylation and nicotinamide inhibition of Sir2 consistent with mutagenesis and enzymatic studies.</p>
},
  year = {2004},
  journal = {Molecular Cell},
  volume = {13},
  number = {5},
  pages = {639-648},
  month = {03/2004},
  isbn = {1097-2765},
  url = {https://www.sciencedirect.com/science/article/pii/S1097276504000826?via\%3Dihub},
  language = {eng},
}