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Bases estructurales de la activación de un receptor GABA metabotrópico
Hamidreza Shaye1,2, Andrii Ishchenko1,2, Jordy Homing Lam1,3
1Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.
Nature
|June 20, 2020
Resumen
Los investigadores visualizaron los estados inactivos y activos de los receptores metabotrópicos de ácido γ-aminobutírico (GABAB) utilizando cryo-EM. Las estructuras revelan cómo la unión agonista y los moduladores alostéricos controlan la señalización del receptor GABAB.
Área de la Ciencia:
- La neurociencia
- Biología estructural
- La bioquímica
Sus antecedentes:
- Los receptores metabotrópicos de ácido γ-aminobutírico (GABAB) son cruciales para modular la actividad sináptica en el sistema nervioso central.
- La disfunción de los receptores GABA sub B está relacionada con trastornos neuropsicológicos como la adicción y la psicosis.
- Los receptores GABAB son receptores acoplados a proteínas G (GPCR) pertenecientes a la clase C, que funcionan como heterodímeros obligados GB1-GB2.
Objetivo del estudio:
- Para aclarar los mecanismos estructurales que subyacen a la activación del receptor GABAB.
- Para visualizar los cambios conformacionales del heterodímero GB1-GB2 tras la unión del ligando.
- Proporcionar información sobre el papel de los moduladores alostéricos positivos en la estabilización del estado activo del receptor.
Principales métodos:
- Para determinar las estructuras de alta resolución se empleó la criomicroscopia electrónica (Cryo-EM).
- Se resolvieron cuatro estados estructurales distintos del heterodímero humano de longitud completa GB1-GB2.
- Las estructuras incluían el estado apo inactivo, los estados intermedios ligados al agonista y un estado activo con un agonista y un modulador alostérico positivo.
Principales resultados:
- La unión del agonista induce el cierre del dominio de la Venus en la subunidad GB1.
- Esto inicia las transiciones conformacionales, acercando los dominios transmembranales.
- Un mecanismo similar a una palanca que involucra el dominio transmembrana GB2 media la señalización aguas abajo.
- Los moduladores alostéricos positivos estabilizan la conformación del receptor activo mediante la unión en la interfaz transmembrana.
Conclusiones:
- El estudio revela los cambios conformacionales dinámicos que rigen la activación del receptor GABAB.
- Los hallazgos aclaran el intrincado mecanismo por el cual los ligandos modulan la función del receptor.
- Las perspectivas estructurales allanan el camino para el desarrollo de terapias dirigidas para afecciones neurológicas y psiquiátricas.
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