Structural basis of Sirtuin 6 inhibition by the hydroxamate trichostatin A - implications for protein deacylase drug development.

Protein lysine deacylases comprise three zinc-dependent families and the NAD(+)-dependent sirtuins Sirt1-7, which contribute to aging-related diseases. Few Sirt6-specific inhibitors are available. Trichostatin A, which belongs to the potent, zinc-chelating hydroxamate inhibitors of zinc-dependent deacylases, was recently found to potently and isoform-specifically inhibit Sirt6. We solved a crystal structure of a Sirt6/ADP-ribose/trichostatin A complex, which reveals nicotinamide pocket and acyl channel as binding site and provides interaction details supporting the development of improved deacylase inhibitors.