[NMR paper] Kinase in Motion: Insights into the Dynamic Nature of p38? by High-Pressure NMR Spectroscopic Studies.

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Kinase in Motion: Insights into the Dynamic Nature of p38? by High-Pressure NMR Spectroscopic Studies.

Kinase in Motion: Insights into the Dynamic Nature of p38? by High-Pressure NMR Spectroscopic Studies.

Chembiochem. 2013 Jul 10;

Authors: Nielsen G, Jonker HR, Vajpai N, Grzesiek S, Schwalbe H

Abstract
Protein kinases are highly dynamic and complex molecules. Here we present high-pressure and relaxation studies of the activated p38? mitogen-activated protein kinase (MAPK). p38? plays a central role in inflammatory diseases such as rheumatoid arthritis and is therefore a highly attractive pharmaceutical target. The combination of high pressure and NMR spectroscopy allowed for a detailed per-residue based assessment of the structural plasticity of p38? and the accessibility of low-lying excited-energy conformations throughout the kinase structure. Such information is uniquely accessible through the combination of liquid-state NMR and high pressure and is of considerable value for the drug discovery process. The interactions of p38? and DFG-in and DFG-out ligands were studied under the application of high pressure, and we demonstrate how we can alter kinase dynamics by pressure in a similar way to what has previously only been observed by ligand binding. Pressure is shown to be a mild and efficient tool for manipulation of intermediate-timescale dynamics.


PMID: 23843149 [PubMed - as supplied by publisher]



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