Molecular tweezers modulate 14-3-3 protein-protein interactions

David Bier, Rolf Rose, Kenny Bravo-Rodriguez, Maria Bartel, Juan Manuel Ramirez-Anguita, Som Dutt, Constanze Wilch, Frank-Gerrit Klärner, Elsa Sanchez-Garcia, Thomas Schrader, Christian Ottmann

Research output: Contribution to journalArticleAcademicpeer-review

154 Citations (Scopus)
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Supramolecular chemistry has recently emerged as a promising way to modulate protein functions, but devising molecules that will interact with a protein in the desired manner is difficult as many competing interactions exist in a biological environment (with solvents, salts or different sites for the target biomolecule). We now show that lysine-specific molecular tweezers bind to a 14-3-3 adapter protein and modulate its interaction with partner proteins. The tweezers inhibit binding between the 14-3-3 protein and two partner proteins--a phosphorylated (C-Raf) protein and an unphosphorylated one (ExoS)--in a concentration-dependent manner. Protein crystallography shows that this effect arises from the binding of the tweezers to a single surface-exposed lysine (Lys214) of the 14-3-3 protein in the proximity of its central channel, which normally binds the partner proteins. A combination of structural analysis and computer simulations provides rules for the tweezers' binding preferences, thus allowing us to predict their influence on this type of protein-protein interactions.

Original languageEnglish
Pages (from-to)234-239
Number of pages6
JournalNature Chemistry
Issue number3
Publication statusPublished - Mar 2013


  • 14-3-3 Proteins/chemistry
  • ADP Ribose Transferases/chemistry
  • Bacterial Toxins/chemistry
  • Biomimetic Materials/chemistry
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Phosphorylation
  • Protein Binding
  • Proto-Oncogene Proteins c-raf/chemistry
  • Recombinant Proteins/chemistry


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