Structure-Based Development of an Affinity Probe for Sirtuin 2

Sirtuins are NAD(+)-dependent protein deacylases that cleave off acetyl groups, as well as other acyl groups, from the ɛ-amino group of lysines in histones and other substrate proteins. Dysregulation of human SIRT2 activity has been associated with the pathogenesis of Cancer, inflammation, and neurodegeneration, thus making SIRT2 a promising target for pharmaceutical intervention. Here, based on a crystal structure of SIRT2 in complex with an optimized Sirtuin rearranging ligand (SirReal) that shows improved potency, water solubility, and cellular efficacy, we present the development of the first Sirt2-selective affinity probe. A slow dissociation of the probe/Enzyme complex offers new applications for SirReals, such as biophysical characterization, fragment-based screening, and affinity pull-down assays. This possibility makes the SirReal probe an important tool for studying Sirtuin biology.