1. A highly specific inhibitor of human p38 MAP kinase binds in the ATP pocket
- Author
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Sheri Rogers, Charles L. Cywin, Liang Tong, Susan Pav, Della White, Kathy Crane, Christopher Pargellis, and Maryanne L. Brown
- Subjects
Models, Molecular ,Pyridines ,Serine threonine protein kinase ,Mitogen-activated protein kinase kinase ,Crystallography, X-Ray ,p38 Mitogen-Activated Protein Kinases ,Biochemistry ,MAP2K7 ,Adenosine Triphosphate ,Structural Biology ,Genetics ,Humans ,Computer Simulation ,c-Raf ,Enzyme Inhibitors ,Protein kinase A ,Binding Sites ,biology ,Cyclin-dependent kinase 2 ,Imidazoles ,Recombinant Proteins ,Calcium-Calmodulin-Dependent Protein Kinases ,Cyclin-dependent kinase complex ,biology.protein ,Mitogen-Activated Protein Kinases ,Casein kinase 2 - Abstract
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.
- Published
- 1997