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Bases estructurales de la activación de GPBAR y el reconocimiento de ácidos biliares

Fan Yang^1,2, Chunyou Mao^3,4, Lulu Guo^1,2

¹Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.

|July 23, 2020

Resumen

Las perspectivas estructurales en el receptor de ácido biliar acoplado a la proteína G (GPBAR) revelan características únicas para el reconocimiento y la señalización de ácido biliar. Estos resultados iluminan el receptor

Área de la Ciencia:

La bioquímica
Biología estructural
Farmacología molecular

Sus antecedentes:

El receptor de ácido biliar acoplado a la proteína G (GPBAR) es crucial para la señalización del ácido biliar y la regulación metabólica.
GPBAR actúa como un eje de señalización clave en el eje de metabolismo hígado-bíl-ácido-microbiota.

Objetivo del estudio:

Determinar las estructuras de criomicroscopía de alta resolución de los complejos GPBAR-Gs.
Para aclarar la base estructural del reconocimiento de ácido biliar y la modulación alostérica por GPBAR.

Principales métodos:

Microscopía cryoelectrónica (cryo-EM) con una resolución de 3 Å.
Estabilización compleja con el ligando de alta afinidad P395 y el derivado de ácido biliar INT-777.

Principales resultados:

Reveló un gran bolsillo de unión de ligando con residuos clave para el reconocimiento de diversos ácidos biliares.
Se identificó un supuesto sitio de unión de ácido biliar alostérico y características estructurales que contribuyen a la señalización sesgada.
Se descubrió una activación atípica de GPBAR y un mecanismo de acoplamiento de proteínas G que involucra redes y motivos de residuos específicos.

Conclusiones:

El estudio proporciona información estructural única sobre la unión de ácido biliar y la regulación alosterica de GPBAR.
Los hallazgos sugieren mecanismos distintos para la comunicación del bolsillo de unión del ligando al sitio de unión de la proteína G en los GPCR.

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