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

8 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
Number of pages5
JournalChemBioChem
Volume19
Issue number6
DOIs
Publication statusPublished - 16 Mar 2018

Keywords

  • Molecular dynamics
  • Molecular recognition
  • Protein binding
  • Protein-protein interactions
  • Supramolecular chemistry
  • Small Molecule Libraries/chemical synthesis
  • Humans
  • Models, Molecular
  • Crystallography, X-Ray
  • 14-3-3 Proteins/antagonists & inhibitors
  • Drug Design
  • Ligands
  • Molecular Structure
  • Peptides/chemical synthesis
  • Binding Sites/drug effects
  • Dimerization
  • molecular dynamics
  • protein binding
  • protein-protein interactions
  • molecular recognition
  • supramolecular chemistry

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