4.8 Article

Structure-Based Development of an Affinity Probe for Sirtuin2

期刊

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 55, 期 6, 页码 2252-2256

出版社

WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201509843

关键词

deacylases; drug design; protein modifications; proteomics; sirtuins

资金

  1. Deutsche Forschungsgemeinschaft (DFG) [Ju295/8-1, Si868/6-1, SFB992: A04 Z02]
  2. Hungarian National Scientific Research Fund [OTKA T-101039, T-112144]

向作者/读者索取更多资源

Sirtuins are NAD(+)-dependent protein deacylases that cleave off acetyl groups, as well as other acyl groups, from the -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.

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