5dy5
Crystal structure of human Sirt2 in complex with a SirReal probe fragment
Structural highlights
FunctionSIR2_HUMAN NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and non-histone proteins. Deacetylates 'Lys-40' of alpha-tubulin. Involved in the control of mitotic exit in the cell cycle, probably via its role in the regulation of cytoskeleton. Deacetylates PCK1, opposing proteasomal degradation. Deacetylates 'Lys-310' of RELA.[1] [2] [3] [4] Publication Abstract from PubMedSirtuins are NAD+ -dependent protein deacylases that cleave off acetyl groups, as well as other acyl groups, from the epsilon-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. Structure-Based Development of an Affinity Probe for Sirtuin 2.,Schiedel M, Rumpf T, Karaman B, Lehotzky A, Gerhardt S, Ovadi J, Sippl W, Einsle O, Jung M Angew Chem Int Ed Engl. 2016 Jan 8. doi: 10.1002/anie.201509843. PMID:26748890[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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