Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Albertstrasse 25, 79104, Freiburg im Breisgau, Germany.
Institute für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Strasse 4, 06120, Halle, Saale, Germany.
Angew Chem Int Ed Engl. 2016 Feb 5;55(6):2252-6. doi: 10.1002/anie.201509843. Epub 2016 Jan 8.
Sirtuins are NAD(+)-dependent protein deacylases that cleave off acetyl groups, as well as other acyl groups, from the ɛ-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.
去乙酰化酶 Sirtuins 是 NAD(+) 依赖的蛋白去酰基酶，能够从组蛋白和其他底物蛋白中赖氨酸的 ε-氨基上切割掉乙酰基和其他酰基。人类 Sirt2 活性的失调与癌症、炎症和神经退行性变的发病机制有关，因此 Sirt2 是药物干预的一个很有前途的靶点。在这里，我们基于 Sirt2 与优化的 Sirtuin 重排配体（SirReal）的复合物的晶体结构，该配体显示出提高的效力、水溶性和细胞功效，提出了第一个 Sirt2 选择性亲和探针的开发。探针/酶复合物的缓慢解离为 SirReal 提供了新的应用，例如生物物理特性分析、基于片段的筛选和亲和下拉测定。这种可能性使 SirReal 探针成为研究 sirtuin 生物学的重要工具。
