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. A molecular tweezer has been shown to bind to the surface of a 14-3-3 protein through a particular lysine residue. This interaction — characterized in detail by protein crystallography and computational modelling — disrupts the protein's binding with partner proteins. These findings ascertain supramolecular chemistry as an enticing tool in chemical biology, here towards modulating protein functions.

Cite this article

Bier, D., Rose, R., Bravo-Rodriguez, K. et al. Molecular tweezers modulate 14-3-3 protein–protein interactions. Nature Chem 5, 234–239 (2013). https://doi.org/10.1038/nchem.1570

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