Structural basis for the high-affinity binding of pyrrolotriazine inhibitors of p38 MAP kinase.
Acta Crystallogr D Biol Crystallogr
; D64(Pt 7): 705-10, 2008 Jul.
Article
em En
| MEDLINE
| ID: mdl-18566506
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Pirróis
/
Benzamidas
/
Proteína Quinase 14 Ativada por Mitógeno
/
Inibidores de Proteínas Quinases
/
Anilidas
Limite:
Humans
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article