Structure-Based Development of an Affinity Probe for Sirtuin2

Schiedel M., Rumpf T., Karaman B., Lehotzky A., Gerhardt S., Ovadi J., ...More

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, vol.55, no.6, pp.2252-2256, 2016 (SCI-Expanded, Scopus)

Abstract

Sirtuins are NAD(+)-dependent protein deacylases that cleave off acetyl groups, as well as other acyl groups, from the -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.