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Mecanismo de regulación de la β2AR por un modulador alostérico positivo intracelular
Xiangyu Liu1, Ali Masoudi2, Alem W Kahsai2
1Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
Science (New York, N.Y.)
|June 29, 2019
Resumen
Los investigadores aclararon la estructura de un receptor acoplado a proteínas G unido a un modulador alostérico positivo. Esto revela cómo los medicamentos alostéricos pueden estabilizar las conformaciones de los receptores para beneficio terapéutico.
Área de la Ciencia:
- Farmacología
- Biología estructural
- La bioquímica
Sus antecedentes:
- Los receptores acoplados a proteínas G (GPCR) son objetivos farmacológicos cruciales, y la mayoría de las terapias actúan en sitios ortostéricos.
- Los sitios alostéricos en los GPCR son menos conocidos y subexploitados terapéuticamente.
- Comprender la modulación alostérica es clave para desarrollar nuevas terapias.
Objetivo del estudio:
- Determinar la estructura cristalina del receptor β2-adrenérgico (β2AR) complejo con un agonista ortostérico y un modulador alostérico positivo (compuesto-6FA).
- Para aclarar el sitio de unión y el mecanismo de acción del compuesto-6FA.
- Para explicar la selectividad del compuesto-6FA para β2AR sobre β1AR.
Principales métodos:
- Cristalografía de rayos X
- Co-cristalización de β2AR con un agonista ortostérico y el compuesto-6FA
- Análisis y comparación estructural
Principales resultados:
- La estructura cristalina reveló que el compuesto 6FA se une a un sitio alostérico en la superficie interna del β2AR.
- Este sitio alostérico está formado por el bucle intracelular 2 y los segmentos transmembrana 3 y 4.
- El compuesto 6FA estabiliza una conformación α-helical del bucle intracelular 2, esencial para el acoplamiento de la proteína G.
- Las diferencias estructurales explican la selectividad observada para β2AR sobre β1AR.
Conclusiones:
- El estudio proporciona una base estructural para la modulación alostérica positiva del β2AR.
- Los ligandos alostéricos pueden estabilizar conformaciones receptoras específicas, ofreciendo nuevas estrategias terapéuticas.
- La naturaleza diversa de los ligandos alostéricos sugiere el potencial para expandir el panorama de descubrimiento de fármacos para los GPCR.
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