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Kinase in Motion : Insights into the Dynamic Nature of p38α by High-Pressure NMR Spectroscopic Studies

Nielsen, Gerd and Jonker, Hendrik R. A. and Vajpai, Navratna and Grzesiek, Stephan and Schwalbe, Harald. (2013) Kinase in Motion : Insights into the Dynamic Nature of p38α by High-Pressure NMR Spectroscopic Studies. ChemBioChem, Vol. 14, H. 14. pp. 1799-1806.

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Official URL: http://edoc.unibas.ch/dok/A6184019

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Abstract

Protein kinases are highly dynamic and complex molecules. Here we present high-pressure and relaxation studies of the activated p38α mitogen-activated protein kinase (MAPK). p38α 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 p38α 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 p38α 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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Grzesiek)
UniBasel Contributors:Grzesiek, Stephan
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Wiley-VCH
ISSN:1439-4227
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:06 Dec 2013 09:35
Deposited On:06 Dec 2013 09:35

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