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Modo de unión conservado de los agonistas y antagonistas inversos de los receptores adrenérgicos beta2 humanos
Daniel Wacker1, Gustavo Fenalti, Monica A Brown
1Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Journal of the American Chemical Society
|July 31, 2010
Resumen
Los estudios estructurales del receptor adrenérgico beta 2 (beta 2 AR) revelan cambios locales menores cuando se unen a diferentes agonistas y antagonistas inversos. Estos hallazgos ayudan a comprender las interacciones de ligandos para el diseño de fármacos.
Área de la Ciencia:
- Biología Estructural Biología estructural.
- Farmacología Farmacología.
- La bioquímica es la bioquímica.
Sus antecedentes:
- Los receptores acoplados a proteínas G (GPCR) son objetivos farmacéuticos clave.
- El receptor adrenérgico beta 2 (beta 2 AR) es ampliamente estudiado dentro de la familia GPCR.
- Estudios previos determinaron estructuras beta(2) AR con agonistas inversos parciales, pero los cambios conformacionales inducidos por ligandos siguen sin estar claros.
Objetivo del estudio:
- Para investigar las diferencias conformacionales inducidas por ligandos en el AR beta.
- Para determinar las estructuras cristalinas de beta(2) AR en complejo con ICI 118,551 y alprenolol.
- Para entender cómo diversos ligandos interactúan con el sitio de unión beta ((2) AR.
Principales métodos:
- La cristalografía de rayos X se utilizó para determinar las estructuras de las construcciones de beta(2) AR diseñadas.
- Se complexionaron tres ligandos distintos con el beta(2) AR: ICI 118,551, un nuevo compuesto, y alprenolol.
- Se realizaron experimentos de acoplamiento cruzado de ligandos de los receptores.
Principales resultados:
- El pliegue general de beta(2) AR se mantuvo consistente en diferentes complejos de ligandos.
- El sitio de unión del ligando acomoda diversos compuestos con solo reordenamientos estructurales locales menores.
- Se observó una red conservada de enlaces de hidrógeno que involucra un motivo hidroxi-amina para todos los ligandos.
Conclusiones:
- El sitio de unión beta(2) AR es adaptable a varias propiedades químicas y farmacológicas de los ligandos.
- Una sola estructura beta 2 AR puede ser adecuada para acoplar una gama de antagonistas y agonistas inversos.
- Las estructuras adicionales de ligando-receptor pueden mejorar el acoplamiento in-silico y la optimización del diseño de fármacos.
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