Crystal structure of p38 mitogen-activated protein kinase.
p38 mitogen-activated protein kinase is activated by environmental stress and cytokines and plays a role in transcriptional regulation and inflammatory responses. The crystal structure of the apo, unphosphorylated form of p38 kinase has been solved at 2.3 A resolution. The fold and topology of p38 is similar to ERK2 (Zhang, F., Strand, A., Robbins, D., Cobb, M. H., and Goldsmith, E. J. (1994) Nature 367, 704-711). The relative orientation of the two domains of p38 kinase is different from that observed in the active form of cAMP-dependent protein kinase. The twist results in a misalignment of the active site of p38, suggesting that the orientation of the domains would have to change before catalysis could proceed. The residues that are phosphorylated upon activation of p38 are located on a surface loop that occupies the peptide binding channel. Occlusion of the active site by the loop, and misalignment of catalytic residues, may account for the low enzymatic activity of unphosphorylated p38 kinase.
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Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139-4211, USA.
Fitzgibbon
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Caron
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Griffith
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Chen
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McCaffrey
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Chambers
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D000595:Amino Acid Sequence; D000818:Animals; D016367:Baculoviridae; D001665:Binding Sites; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis / Q000737:chemistry*; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D018411:Spodoptera; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D011994:Recombinant Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases