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Bases estructurales del reconocimiento de ligandos y la autoactivación de la GPR52 huérfana
Xi Lin1,2,3,4, Mingyue Li2,3,4, Niandong Wang1,2,3,4
1iHuman Institute, ShanghaiTech University, Shanghai, China.
Nature
|February 21, 2020
Resumen
El receptor acoplado a la proteína G 52 (GPR52) se activa a través de un mecanismo interno, no requiriendo ligandos externos para una función completa cuando se acopla con la proteína Gs. Este hallazgo ayuda a comprender los receptores autoactivados y guía el descubrimiento de medicamentos para trastornos neurológicos.
Área de la Ciencia:
- Biología estructural
- La neurociencia
- Farmacología
Sus antecedentes:
- El receptor acoplado a la proteína G 52 (GPR52) es un receptor huérfano expresado en el cerebro implicado en la enfermedad de Huntington y trastornos psiquiátricos.
- La señalización de GPR52 involucra principalmente a la proteína Gs, pero su mecanismo de acoplamiento preciso y los requisitos de activación siguen sin estar claros.
Objetivo del estudio:
- Para aclarar la base estructural de la activación de GPR52 y el acoplamiento de la proteína Gs.
- Investigar el papel de los bucles extracelulares y los posibles sitios de unión al ligando en la función de GPR52.
Principales métodos:
- Determinación estructural de alta resolución del GPR52 humano en varios estados (libre de ligandos, acoplado a Gs, ligado a ligandos).
- Análisis de las interacciones receptor-proteína e identificación de las características estructurales clave involucradas en la activación.
Principales resultados:
- El bucle extracelular 2 actúa como un agonista intrínseco, ocupando la bolsa de unión ortostérica y confiriendo una alta actividad basal.
- GPR52 logra la activación completa en el acoplamiento Gs, independientemente de los agonistas externos.
- Un bolsillo lateral distinto sugiere el potencial de unión al ligando alostérico.
Conclusiones:
- GPR52 exhibe autoactivación, con el bucle extracelular 2 jugando un papel crucial.
- Los hallazgos proporcionan un marco estructural para la comprensión de las GPCR autoactivadas.
- Esta investigación puede guiar el desarrollo de nuevas terapias dirigidas a GPR52 para afecciones neurológicas y psiquiátricas.
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