A highly specific inhibitor of human p38 MAP kinase binds in the ATP pocket

Nat Struct Biol. 1997 Apr;4(4):311-6. doi: 10.1038/nsb0497-311.


The crystal structure of human p38 mitogen-activated protein (MAP) kinase in complex with a potent and highly specific pyridinyl-imidazole inhibitor has been determined at 2.0 A 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 the ATP pocket. A hydrogen bond is made between the pyridyl nitrogen of the inhibitor and the main chain amido nitrogen of residue 109, analogous to the interaction from the N1 atom of ATP. The crystal structure provides possible explanations for the specificity of this class of inhibitors. Other protein kinase inhibitors may achieve their specificity through a similar mechanism. The structure also reveals a possible second binding site for this inhibitor, with currently unknown function.

Publication types

  • Comparative Study

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Binding Sites
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors*
  • Calcium-Calmodulin-Dependent Protein Kinases / chemistry*
  • Computer Simulation
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemistry*
  • Humans
  • Imidazoles / chemistry*
  • Mitogen-Activated Protein Kinases*
  • Models, Molecular
  • Pyridines / chemistry*
  • Recombinant Proteins / chemistry
  • p38 Mitogen-Activated Protein Kinases


  • Enzyme Inhibitors
  • Imidazoles
  • Pyridines
  • Recombinant Proteins
  • Adenosine Triphosphate
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580