A HIGHLY SPECIFIC INHIBITOR OF HUMAN P38 MAP KINASE BINDS IN THE ATP POCKET

The crystal structure of human p38 mitogen-activated protein (MAP) kin ase in complex with a potent and highly specific pyridinyl-imidazole i nhibitor has been determined at 2.0 Angstrom resolution. The structure of the kinase, which is in its unphosphorylated state, is similar to that of the closely-related ERK2. The inhibitor molecule is bound in t he ATP pocket. A hydrogen bond is made between the pyridyl nitrogen of the inhibitor and the main chain amido nitrogen of residue 109, analo gous to the interaction from the N1 atom of ATP. The crystal structure provides possible explanations for the specificity of this class of i nhibitors. Other protein kinase inhibitors may achieve their specifici ty through a similar mechanism. The structure also reveals a possible second binding site for this inhibitor, with currently unknown functio n.