title: Molecular tweezers modulate 14-3-3 protein-protein interactions.
abstract: 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.
authors: Chemical Genomics Centre of the Max-Planck-Society, Otto-Hahn-Strasse 15, 44227 Dortmund, Germany.
authors: David
authors: D
authors: Bier
authors: Rolf
authors: R
authors: Rose
authors: Kenny
authors: K
authors: Bravo-Rodriguez
authors: Maria
authors: M
authors: Bartel
authors: Juan Manuel
authors: JM
authors: Ramirez-Anguita
authors: Som
authors: S
authors: Dutt
authors: Constanze
authors: C
authors: Wilch
authors: Frank-Gerrit
authors: FG
authors: Klärner
authors: Elsa
authors: E
authors: Sanchez-Garcia
authors: Thomas
authors: T
authors: Schrader
authors: Christian
authors: C
authors: Ottmann
mesh_terms: D048948:14-3-3 Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D036002:ADP Ribose Transferases / Q000737:chemistry / Q000378:metabolism; D001427:Bacterial Toxins / Q000737:chemistry / Q000378:metabolism; D040761:Biomimetic Materials / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D010766:Phosphorylation; D011485:Protein Binding; D019908:Proto-Oncogene Proteins c-raf / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D001427:Bacterial Toxins; D011994:Recombinant Proteins; C572235:YWHAZ protein, human; D036002:ADP Ribose Transferases; C444820:exoenzyme S; D019908:Proto-Oncogene Proteins c-raf