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Activación de la proteína G por un receptor metabotrópico del glutamato
Alpay B Seven1, Ximena Barros-Álvarez1, Marine de Lapeyrière2
1Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
Nature
|July 1, 2021
Resumen
Los receptores acoplados a la proteína G (GPCR) de la familia C funcionan como dímeros. Este estudio revela cómo la activación del receptor metabotrópico de glutamato 2 (mGlu2) reorganiza los dominios transmembrana para permitir el acoplamiento de la proteína G a través de un nuevo mecanismo.
Área de la Ciencia:
- La bioquímica
- Biología estructural
- Farmacología molecular
Sus antecedentes:
- Los receptores acoplados a la proteína G de la familia C (GPCR) son dímeros obligados cruciales para la transducción de señales.
- La unión del ligando a los dominios extracelulares desencadena la activación de la proteína G a través de dominios transmembrana (TM) a través de mecanismos poco conocidos.
Objetivo del estudio:
- Para aclarar los mecanismos estructurales de la activación de la proteína G por la familia C GPCRs.
- Determinar la estructura de los homodímeros del receptor metabotrópico del glutamato 2 (mGlu2) en complejo con las proteínas Gi.
Principales métodos:
- Cristalografía de rayos X para obtener estructuras de alta resolución.
- Análisis de los homodímeros mGlu2 en estados funcionales distintos.
- Caracterización estructural de los complejos mGlu2-Gi.
Principales resultados:
- Las estructuras revelan reordenamientos extensos en los dominios TM tras la activación extracelular, formando una interfaz asimétrica TM6-TM6.
- Se observa el acoplamiento Gi a mGlu2 inactivo, pero la transición libre de nucleótidos requiere la interfaz TM6-TM6 en estado activo.
- El acoplamiento de la proteína G involucra los bucles intracelulares 2 y 3 y el extremo C, distinto de la apertura TM6 observada en otras familias de GPCR.
Conclusiones:
- Se propone un nuevo mecanismo para la activación de la proteína G por los GPCR de la familia C, que implica cambios conformacionales globales y locales.
- Los hallazgos proporcionan información sobre la señalización alostérica de mGlu2 y los receptores relacionados.
- Este trabajo amplía la comprensión de los paradigmas de activación de GPCR.
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