Crystal structures of SIRT3 reveal that the α2-α3 loop and α3-helix affect the interaction with long-chain acyl lysine.

SIRT1-7 play important roles in many biological processes and age-related diseases. In addition to a NAD(+) -dependent deacetylase activity, they can catalyze several other reactions, including the hydrolysis of long-chain fatty acyl lysine. To study the binding modes of sirtuins to long-chain acyl lysines, we solved the crystal structures of SIRT3 bound to either a H3K9-myristoylated- or a H3K9-palmitoylated peptide. Interaction of SIRT3 with the palmitoyl group led to unfolding of the α3-helix. The myristoyl and palmitoyl groups bind to the C-pocket and an allosteric site near the α3-helix, respectively. We found that the residues preceding the α3-helix determine the size of the C-pocket. The flexibility of the α2-α3 loop and the plasticity of the α3-helix affect the interaction with long-chain acyl lysine.