Editorial Volume 5, Issue 3 pp 142—143

Figure 1. Model of allosteric activation of SIRT1 by sirtuin activating compounds (STACs). (A) SIRT1 acting on a substrate with a hydrophobic signature (yellow) in the absence of a STAC. (B) Binding of a STAC alters the N-terminal structure of SIRT1 but the absence of hydrophobic residues C-terminal to the acetyl-lysine on the substrate prevents activation by STACs. (C) The aminomethycoumarin group on the Fluor-de-Lys peptide substrate mimics hydrophobic residues of natural substrates, facilitating activation by STACs. (D) Substrate contains hydrophobic residues C-terminal to the acetyl-lysine thus allowing STAC-induced activation. Mutation of E230 allows STACs to bind to SIRT1 but abolishes STAC-mediated allosteric activation.