Structural basis for the high-affinity binding of pyrrolotriazine inhibitors of p38 MAP kinase.
The crystal structure of unphosphorylated p38alpha MAP kinase complexed with a representative pyrrolotriazine-based inhibitor led to the elucidation of the high-affinity binding mode of this class of compounds at the ATP-binding site. The ligand binds in an extended conformation, with one end interacting with the adenine-pocket hinge region, including a hydrogen bond from the carboxyl O atom of Met109. The other end of the ligand interacts with the hydrophobic pocket of the binding site and with the backbone N atom of Asp168 in the DFG activation loop. Addition of an extended benzylmorpholine group forces the DFG loop to flip out of position and allows the ligand to make additional interactions with the protein.
Sack
John S
JS
Department of Macromolecular Crystallography, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA. john.sack@bms.com
Kish
Kevin F
KF
Pokross
Matthew
M
Xie
Dianlin
D
Duke
Gerald J
GJ
Tredup
Jeffrey A
JA
Kiefer
Susan E
SE
Newitt
John A
JA
D000813:Anilides / Q000737:chemistry*; D001549:Benzamides / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry*
D000813:Anilides; D001549:Benzamides; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D048308:Mitogen-Activated Protein Kinase 14