Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 1 de 1
Filtrar
Más filtros











Base de datos
Asunto principal
Intervalo de año de publicación
1.
PLoS One ; 7(5): e33643, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22606221

RESUMEN

Peroxisome proliferator activated receptors (PPARs δ, α and γ) are closely related transcription factors that exert distinct effects on fatty acid and glucose metabolism, cardiac disease, inflammatory response and other processes. Several groups developed PPAR subtype specific modulators to trigger desirable effects of particular PPARs without harmful side effects associated with activation of other subtypes. Presently, however, many compounds that bind to one of the PPARs cross-react with others and rational strategies to obtain highly selective PPAR modulators are far from clear. GW0742 is a synthetic ligand that binds PPARδ more than 300-fold more tightly than PPARα or PPARγ but the structural basis of PPARδ:GW0742 interactions and reasons for strong selectivity are not clear. Here we report the crystal structure of the PPARδ:GW0742 complex. Comparisons of the PPARδ:GW0742 complex with published structures of PPARs in complex with α and γ selective agonists and pan agonists suggests that two residues (Val312 and Ile328) in the buried hormone binding pocket play special roles in PPARδ selective binding and experimental and computational analysis of effects of mutations in these residues confirms this and suggests that bulky substituents that line the PPARα and γ ligand binding pockets as structural barriers for GW0742 binding. This analysis suggests general strategies for selective PPARδ ligand design.


Asunto(s)
PPAR delta/química , PPAR delta/metabolismo , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Sitios de Unión/genética , Cristalografía por Rayos X , Células Hep G2 , Humanos , Ligandos , Modelos Moleculares , Simulación de Dinámica Molecular , Mutagénesis Sitio-Dirigida , PPAR alfa/química , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR delta/agonistas , PPAR delta/genética , PPAR gamma/química , PPAR gamma/genética , PPAR gamma/metabolismo , Conformación Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homología de Secuencia de Aminoácido , Tiazoles/química , Tiazoles/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA