Rational design, binding studies and crystal structure evaluation of the first ligand targeting the dimerization Interface of the 14-3-3ζ adapter protein

Martin Ehlers, Jean Noël Grad, Sumit Mittal, David Bier, Marcel Mertel, Ludwig Ohl, Maria Bartel, Jeroen Briels, Marius Heimann, Christian Ottmann, Elsa Sanchez-Garcia, Daniel Hoffmann, Carsten Schmuck

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)

Abstract

14-3-3 Proteins play a central role in signalling pathways in cells: they interact as gatekeeper proteins with a huge number of binding partners. Their function as hub for intracellular communication can explain why these adapter proteins are associated with a wide range of diseases. How they control the various cellular mechanisms is still unclear, but it is assumed that the dimeric nature of the 14-3-3 proteins plays a key role in their activity. Here, we present, to the best of our knowledge, the first example of a small molecule binding to the 14-3-3ζ dimerisation interface. This compound was designed by rational in silico optimisation of a peptidic ligand identified from biochemical screening of a peptidic library, and the binding was characterised by UV/Vis spectroscopy, microscale thermophoresis, multiscale simulations, and X-ray crystallography.

Original languageEnglish
Pages (from-to)591-595
JournalChemBioChem
Volume19
Issue number6
DOIs
Publication statusPublished - 16 Mar 2018

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14-3-3 Proteins
Dimerization
Crystal structure
Thermophoresis
Ligands
X ray crystallography
X Ray Crystallography
Ultraviolet spectroscopy
Computer Simulation
Libraries
Spectrum Analysis
Screening
Proteins
Molecules
Communication

Keywords

  • Molecular dynamics
  • Molecular recognition
  • Protein binding
  • Protein-protein interactions
  • Supramolecular chemistry

Cite this

Ehlers, Martin ; Grad, Jean Noël ; Mittal, Sumit ; Bier, David ; Mertel, Marcel ; Ohl, Ludwig ; Bartel, Maria ; Briels, Jeroen ; Heimann, Marius ; Ottmann, Christian ; Sanchez-Garcia, Elsa ; Hoffmann, Daniel ; Schmuck, Carsten. / Rational design, binding studies and crystal structure evaluation of the first ligand targeting the dimerization Interface of the 14-3-3ζ adapter protein. In: ChemBioChem. 2018 ; Vol. 19, No. 6. pp. 591-595.
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Ehlers, M, Grad, JN, Mittal, S, Bier, D, Mertel, M, Ohl, L, Bartel, M, Briels, J, Heimann, M, Ottmann, C, Sanchez-Garcia, E, Hoffmann, D & Schmuck, C 2018, 'Rational design, binding studies and crystal structure evaluation of the first ligand targeting the dimerization Interface of the 14-3-3ζ adapter protein', ChemBioChem, vol. 19, no. 6, pp. 591-595. https://doi.org/10.1002/cbic.201700588

Rational design, binding studies and crystal structure evaluation of the first ligand targeting the dimerization Interface of the 14-3-3ζ adapter protein. / Ehlers, Martin; Grad, Jean Noël; Mittal, Sumit; Bier, David; Mertel, Marcel; Ohl, Ludwig; Bartel, Maria; Briels, Jeroen; Heimann, Marius; Ottmann, Christian; Sanchez-Garcia, Elsa; Hoffmann, Daniel; Schmuck, Carsten.

In: ChemBioChem, Vol. 19, No. 6, 16.03.2018, p. 591-595.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - Mertel, Marcel

AU - Ohl, Ludwig

AU - Bartel, Maria

AU - Briels, Jeroen

AU - Heimann, Marius

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AU - Sanchez-Garcia, Elsa

AU - Hoffmann, Daniel

AU - Schmuck, Carsten

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