5dy4
Crystal structure of human Sirt2 in complex with a brominated 2nd generation SirReal inhibitor and NAD+
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 but also other acyl groups from the epsilon-amino group of lysines in histones and other substrate proteins. Dysregulation of human Sirt2 (hSirt2) activity has been associated with the pathogenesis of cancer, inflammation, and neurodegeneration, which makes the modulation of hSirt2 activity a promising strategy for pharmaceutical intervention. The sirtuin rearranging ligands (SirReals) have recently been discovered by us as highly potent and isotype-selective hSirt2 inhibitors. Here, we present a well-defined structure-activity relationship study, which rationalizes the unique features of the SirReals and probes the limits of modifications on this scaffold regarding inhibitor potency. Moreover, we present a crystal structure of hSirt2 in complex with an optimized SirReal derivative that exhibits an improved in vitro activity. Lastly, we show cellular hyperacetylation of the hSirt2 targeted tubulin caused by our improved lead structure. Aminothiazoles as Potent and Selective Sirt2 Inhibitors: A Structure-Activity Relationship Study.,Schiedel M, Rumpf T, Karaman B, Lehotzky A, Olah J, Gerhardt S, Ovadi J, Sippl W, Einsle O, Jung M J Med Chem. 2016 Jan 7. PMID:26696402[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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