5DY4

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

5DY4 の概要

• エントリーDOI: 10.2210/pdb5dy4/pdb
• 分子名称: 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)
• 機能のキーワード: hydrolase, hydrolase inhibitor complex
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus. Isoform 1: Cytoplasm . Isoform 2: Cytoplasm . Isoform 5: Cytoplasm : Q8IXJ6
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35645.01

構造登録者

Rumpf, T.,Gerhardt, S.,Einsle, O.,Jung, M. (登録日: 2015-09-24, 公開日: 2016-01-13, 最終更新日: 2024-01-10)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.77 Å)