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Mecanismo de activación del dímero GPCR fúngico de la clase D Ste2

Vaithish Velazhahan¹, Ning Ma², Nagarajan Vaidehi²

¹MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, UK.

|March 17, 2022

Resumen

El receptor acoplado a la proteína G de los hongos (GPCR) Ste2 se activa de manera diferente a los GPCR de los mamíferos. Los estudios estructurales revelan movimientos únicos de las hélices transmembrana H6 y H7 al unirse al agonista, facilitando el acoplamiento de la proteína G.

Área de la Ciencia:

Biología estructural
La bioquímica
Farmacología molecular

Sus antecedentes:

El GPCR Ste2 de la clase D1 de hongos presenta características estructurales y de acoplamiento únicas en comparación con los GPCR de mamíferos.
Ste2 carece de motivos conservados (DRY, PIF, NPXXY) cruciales para la activación de la GPCR de clase A, lo que sugiere un mecanismo distinto.

Objetivo del estudio:

Para aclarar el mecanismo de activación de Saccharomyces cerevisiae Ste2.
Determinar la base estructural para el acoplamiento de proteínas G en la etapa 2.

Principales métodos:

Determinación de las estructuras de Ste2 mediante cristalografía de rayos X.
Análisis de las conformaciones Ste2 unidas a un agonista (factor α), un antagonista y sin ligando.

Principales resultados:

El receptor Ste2 inactivo tiene una hélice H7 no estructurada que bloquea el sitio de acoplamiento de la proteína G.
La unión del agonista induce el movimiento hacia afuera de H6 y H7 extracelularmente.
Intracelularmente, H7 se mueve hacia afuera, desbloqueando el sitio, mientras que H6 se mueve hacia adentro, facilitando el acoplamiento de la proteína G.

Conclusiones:

La activación de Ste2 implica un nuevo mecanismo distinto de otros GPCR.
Los movimientos únicos de las hélices transmembrana H6 y H7 son críticos para el acoplamiento de la proteína G en Ste2.

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