Intrinsic Allosteric Inhibition of Signaling Proteins by Targeting Rare Interaction States Detected by High-Pressure NMR Spectroscopy

A new type of allosteric inhibition by small molecules is proposed that should be applicable to all proteins involved intrinsically in protein–protein interactions. It is based on targeting their rare interaction states that can be detected by high‐pressure NMR spectroscopy (see picture). An example...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2013-12, Vol.52 (52), p.14242-14246
Main Authors: Kalbitzer, Hans Robert, Rosnizeck, Ina C., Munte, Claudia E., Narayanan, Sunilkumar Puthenpurackal, Kropf, Veronika, Spoerner, Michael
Format: Article
Language:English
Subjects:
allosteric inhibition
Allosteric Regulation
conformational states
Drug Design
Effectors
high-pressure NMR spectroscopy
Inhibition
Magnetic Resonance Spectroscopy - methods
NMR spectroscopy
Pictures
Proteins
Proteins - chemistry
Ras protein
Signal Transduction
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Summary:A new type of allosteric inhibition by small molecules is proposed that should be applicable to all proteins involved intrinsically in protein–protein interactions. It is based on targeting their rare interaction states that can be detected by high‐pressure NMR spectroscopy (see picture). An example is the Ras‐protein where the protein–protein interaction of Ras with effectors can be modulated by small compounds that bind to the conformational states 1(T) or 1(0).
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201305741