title: Kinase in motion: insights into the dynamic nature of p38α by high-pressure NMR spectroscopic studies.
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.
authors.affiliation: Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Johann Wolfgang Goethe University, Max-von-Laue-Strasse 7, 60438 Frankfurt am Main (Germany).
authors.forename: Gerd
authors.initials: G
authors.lastname: Nielsen
authors.forename: Hendrik R A
authors.initials: HR
authors.lastname: Jonker
authors.forename: Navratna
authors.initials: N
authors.lastname: Vajpai
authors.forename: Stephan
authors.initials: S
authors.lastname: Grzesiek
authors.forename: Harald
authors.initials: H
authors.lastname: Schwalbe
mesh_terms: D000818:Animals; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D011312:Pressure; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013696:Temperature
chemical_list: D011994:Recombinant Proteins; D048308:Mitogen-Activated Protein Kinase 14
keywords: DFG loop; NMR spectroscopy; high-pressure chemistry; p38alpha; relaxation