Inhibitors bound to p38 and ERK2

The structural basis for the exceptional selectivity of the anti-inflammatory pyridinylimidazole and its analogs (SB compounds) for the MAP kinase p38, and the relative selectivity of olomoucine for ERK2 has been elucidated by comparative crystallography. The crystal structures of four SB compounds in complex with p38, one SB compound and olomoucine in complex with ERK2 have been determined. While all the inhibitors bind to the ATP site, the SB inhibitors bind in an extended pocket in the active site and are complementary to the open domain structure of the low activity form of p38. The relatively closed domain structure of ERK2 accommodates the smaller olomoucine. The analysis reveals that the unique kinase-inhibitor interactions observed in these complexes derive 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 of the kinases. This structural information directly facilitates design of better MAP kinase inhibitors in therapeutic treatments of inflammation and other diseases.