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

MPG-Autoren
http://pubman.mpdl.mpg.de/cone/persons/resource/persons101523

Bravo-Rodriguez,  Kenny
Research Group Sánchez-García, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons132987

Ramirez-Anguita,  Juan Manuel
Research Group Sánchez-García, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons101503

Sánchez-García,  Elsa
Research Group Sánchez-García, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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nchem.1570-s1.pdf
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Zitation

Bier, D., Rose, R., Bravo-Rodriguez, K., Bartel, M., Ramirez-Anguita, J. M., Dutt, S., et al. (2013). Molecular tweezers modulate 14-3-3 protein–protein interactions. Nature Chemistry, 5(3), 234-239. doi:10.1038/nchem.1570.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-0014-A2D5-8
Zusammenfassung
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.