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

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 th...

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Veröffentlicht in:	Nature chemistry Jg. 5; H. 3; S. 234 - 239
Hauptverfasser:	Bier, David, Rose, Rolf, Bravo-Rodriguez, Kenny, Bartel, Maria, Ramirez-Anguita, Juan Manuel, Dutt, Som, Wilch, Constanze, Klärner, Frank-Gerrit, Sanchez-Garcia, Elsa, Schrader, Thomas, Ottmann, Christian
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 01.03.2013 Nature Publishing Group
Schlagworte:	14-3-3 protein 14-3-3 Proteins - chemistry 14-3-3 Proteins - genetics 14-3-3 Proteins - metabolism 639/638/541 639/638/92/96 Adapter proteins Adapters ADP Ribose Transferases - chemistry ADP Ribose Transferases - metabolism Amino acids Analytical Chemistry Bacterial Toxins - chemistry Bacterial Toxins - metabolism Binding Biochemistry Biology Biomimetic Materials - chemistry Biomimetic Materials - metabolism Biomolecules Chemistry Chemistry/Food Science Computer simulation Crystallography Enzymes Humans Inorganic Chemistry Kinases Ligands Lysine Mathematical models Mechanics Models, Molecular Molecular Conformation Organic Chemistry Phosphates Phosphorylation Physical Chemistry Physiology Protein Binding Protein interaction Proteins Proto-Oncogene Proteins c-raf - chemistry Proto-Oncogene Proteins c-raf - metabolism Recombinant Proteins - chemistry Recombinant Proteins - genetics Recombinant Proteins - metabolism Salts Solvents Structural analysis Germany
ISSN:	1755-4330, 1755-4349, 1755-4349
Online-Zugang:	Volltext
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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. 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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1755-4330 1755-4349 1755-4349
DOI:	10.1038/nchem.1570