The structural basis for the specificity of pyridinylimidazole inhibitors of p38 MAP kinase.
BACKGROUND
The p38 mitogen-activated protein (MAP) kinase regulates signal transduction in response to environmental stress. Pyridinylimidazole compounds are specific inhibitors of p38 MAP kinase that block the production of the cytokines interleukin-1beta and tumor necrosis factor alpha, and they are effective in animal models of arthritis, bone resorption and endotoxin shock. These compounds have been useful probes for studying the physiological functions of the p38-mediated MAP kinase pathway.


RESULTS
We report the crystal structure of a novel pyridinylimidazole compound complexed with p38 MAP kinase, and we demonstrate that this compound binds to the same site on the kinase as does ATP. Mutagenesis showed that a single residue difference between p38 MAP kinase and other MAP kinases is sufficient to confer selectivity among pyridinylimidazole compounds.


CONCLUSIONS
Our results reveal how pyridinylimidazole compounds are potent and selective inhibitors of p38 MAP kinase but not other MAP kinases. It should now be possible to design other specific inhibitors of activated p38 MAP kinase using the structure of the nonphosphorylated enzyme.
Wilson
K P
KP
Vertex Pharmaceuticals Incorporated 130 Waverly Street, Cambridge, MA 02139-4211, USA.
McCaffrey
P G
PG
Hsiao
K
K
Pazhanisamy
S
S
Galullo
V
V
Bemis
G W
GW
Fitzgibbon
M J
MJ
Caron
P R
PR
Murcko
M A
MA
Su
M S
MS
D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases
C107383:4-(4-fluorophenyl)-1-(4-piperidinyl)-5-(4-pyridyl)-imidazole; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D000255:Adenosine Triphosphate; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole