2. Academic Validation
  3. Structure-Based Development of an Affinity Probe for Sirtuin 2

Structure-Based Development of an Affinity Probe for Sirtuin 2

  • Angew Chem Int Ed Engl. 2016 Feb 5;55(6):2252-6. doi: 10.1002/anie.201509843.
Matthias Schiedel 1,  Tobias Rumpf 1,  Berin Karaman 2,  Attila Lehotzky 3,  Stefan Gerhardt 4,  Judit Ovádi 3,  Wolfgang Sippl 2,  Oliver Einsle 4,  Manfred Jung 5
Affiliations

Affiliations

  • 1 Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Albertstrasse 25, 79104, Freiburg im Breisgau, Germany.
  • 2 Institute für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Strasse 4, 06120, Halle, Saale, Germany.
  • 3 Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok körútja 2, H-1117, Budapest, Hungary.
  • 4 Institute für Biochemie und BIOSS Centre for Biological, Signaling Studies, Albert-Ludwigs-Universität Freiburg, Albertstrasse 21, 79104, Freiburg im Breisgau, Germany.
  • 5 Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Albertstrasse 25, 79104, Freiburg im Breisgau, Germany. manfred.jung@pharmazie.uni-freiburg.de.
PMID: 26748890 DOI: 10.1002/anie.201509843
Abstract

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.

Keywords

deacylases; drug design; protein modifications; proteomics; sirtuins.

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