CRYSTAL-STRUCTURE OF P38 MITOGEN-ACTIVATED PROTEIN-KINASE

p38 mitogen-activated protein kinase is activated by environmental str ess and cytokines and plays a role in transcriptional regulation and i nflammatory responses, The crystal structure of the ape, unphosphoryla ted form of p38 kinase has been solved at 2.3 Angstrom resolution. The fold and topology of p38 is similar to ERK2 (Zhang, F., Strand, A,, R obbins, D., Cobb, MI H., and Goldsmith, E. J. (1994) Nature 367, 704-7 11), The relative orientation of the two domains of p38 kinase is diff erent 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 b efore catalysis could proceed, The residues that are phosphorylated up on activation of p38 are located on a surface loop that occupies the p eptide 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.