5DY4

Crystal structure of human Sirt2 in complex with a brominated 2nd generation SirReal inhibitor and NAD+

Summary for 5DY4

• Entry DOI: 10.2210/pdb5dy4/pdb
• Descriptor: NAD-dependent protein deacetylase sirtuin-2, ZINC ION, N-{5-[(7-bromonaphthalen-1-yl)methyl]-1,3-thiazol-2-yl}-2-[(4,6-dimethylpyrimidin-2-yl)sulfanyl]acetamide, ... (5 entities in total)
• Functional Keywords: hydrolase, hydrolase inhibitor complex
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus. Isoform 1: Cytoplasm . Isoform 2: Cytoplasm . Isoform 5: Cytoplasm : Q8IXJ6
• Total number of polymer chains: 1
• Total formula weight: 35645.01

Authors

Rumpf, T.,Gerhardt, S.,Einsle, O.,Jung, M. (deposition date: 2015-09-24, release date: 2016-01-13, Last modification date: 2024-01-10)

Primary citation

Schiedel, M.,Rumpf, T.,Karaman, B.,Lehotzky, A.,Olah, J.,Gerhardt, S.,Ovadi, J.,Sippl, W.,Einsle, O.,Jung, M.
Aminothiazoles as Potent and Selective Sirt2 Inhibitors: A Structure-Activity Relationship Study.
J.Med.Chem., 59:1599-1612, 2016

PubMed Abstract: Sirtuins are NAD(+)-dependent protein deacylases that cleave off acetyl but also other acyl groups from the ε-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.

PubMed: 26696402
DOI: 10.1021/acs.jmedchem.5b01517

Experimental method

X-RAY DIFFRACTION (1.77 Å)