Structure-based development of an affinity probe for sirtuin 2

Matthias Schiedel, Tobias Rumpf, Berin Karaman, A. Lehotzky, Stefan Gerhardt, J. Ovádi, Wolfgang Sippl, Oliver Einsle, Manfred Jung

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Sirtuins are NAD+-dependent protein deacylases that cleave off acetyl groups, as well as other acyl groups, from the É?-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. A new probe for drug design: An affinity probe for Sirt2 has been developed that shows excellent selectivity and potency. The slow dissociation rate of the enzyme-ligand complex enables new applications, such as biolayer interferometry, and pull-down assays for sirtuin rearranging ligands.

Original languageEnglish
Pages (from-to)2252-2256
Number of pages5
JournalAngewandte Chemie - International Edition
Volume55
Issue number6
DOIs
Publication statusPublished - Feb 5 2016

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Sirtuin 2
Ligands
Assays
Enzymes
Sirtuins
Proteins
Interferometry
Pharmaceutical Preparations
NAD
Histones
Drug products
Lysine
Screening
Solubility
Crystal structure
Water
Substrates

Keywords

  • deacylases
  • drug design
  • protein modifications
  • proteomics
  • sirtuins

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis

Cite this

Structure-based development of an affinity probe for sirtuin 2. / Schiedel, Matthias; Rumpf, Tobias; Karaman, Berin; Lehotzky, A.; Gerhardt, Stefan; Ovádi, J.; Sippl, Wolfgang; Einsle, Oliver; Jung, Manfred.

In: Angewandte Chemie - International Edition, Vol. 55, No. 6, 05.02.2016, p. 2252-2256.

Research output: Contribution to journalArticle

Schiedel, M, Rumpf, T, Karaman, B, Lehotzky, A, Gerhardt, S, Ovádi, J, Sippl, W, Einsle, O & Jung, M 2016, 'Structure-based development of an affinity probe for sirtuin 2', Angewandte Chemie - International Edition, vol. 55, no. 6, pp. 2252-2256. https://doi.org/10.1002/anie.201509843
Schiedel, Matthias ; Rumpf, Tobias ; Karaman, Berin ; Lehotzky, A. ; Gerhardt, Stefan ; Ovádi, J. ; Sippl, Wolfgang ; Einsle, Oliver ; Jung, Manfred. / Structure-based development of an affinity probe for sirtuin 2. In: Angewandte Chemie - International Edition. 2016 ; Vol. 55, No. 6. pp. 2252-2256.
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