Structure-based development of an affinity probe for sirtuin 2

Schiedel, M. and Rumpf, T. and Karaman, B. and Lehotzky, Attila and Gerhardt, S. and Ovádi, Judit (2016) Structure-based development of an affinity probe for sirtuin 2. ANGEWANDTE CHEMIE INTERNATIONAL EDITION, 55 (6). pp. 2252-2256. ISSN 1433-7851

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Abstract

Sirtuins are NAD+-dependent protein deacylases that cleave off acetyl groups, as well as other acyl groups, from the É?-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. A new probe for drug design: An affinity probe for Sirt2 has been developed that shows excellent selectivity and potency. The slow dissociation rate of the enzyme-ligand complex enables new applications, such as biolayer interferometry, and pull-down assays for sirtuin rearranging ligands. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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