Comparative crystallography of map kin a se/inhibitor complexes reveals origin of selectivity of pyridinylimidazoie compounds and olomoucine

The anti-inflammatory pyridinylimidazole and its analogs (SB compounds) are potent and highly selective inhibitors for the MAP kinase p38, but not for its closely-related family member ERK2. The crystal structures of four SB compounds in complex with p38, one SB compound and the cyclin-dependent kinase inhibitor olomoucine in complex with ERK2 have been determined. All the inhibitors bind to the ATP binding site of the MAP kinases. However, the detailed interactions between the inhibitors and the proteins are distinct. The SB inhibitors bind in an extended pocket in the active site and are complementary to the open domain structure of low activity form of p38. The relatively closed domain structure of ERK2 accommodates the smaller olomoucine. The comparative crystallography of the six MAP kinase/inhibitor complexes reveals that the inhibition specificity derives from 1) amino acid replacements in the active site, and 2) replacements distant from the active site that affect the shape and size of the domain interface. This structural information not only provides a molecular basis underlying the origin of specificity of these ATP-site directed inhibitors, but also facilitates design of better MAP kinase inhibitors in therapeutic treatments of inflammations and other diseases.