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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
La estructura cristalina del activador de la adenilil ciclasa Gsalphapha es muy similar a la del activador Gsalpha
R K Sunahara1, J J Tesmer, A G Gilman
1Department of Pharmacology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-9041, USA.
Science (New York, N.Y.)
|January 7, 1998
Resumen
La estructura cristalina de Gsalpha, una proteína de señalización clave, fue revelada utilizando GTPgammaS. Las diferencias en su estructura en comparación con Gialpha explican la especificidad del efector y las interacciones con los reguladores de señalización.
Área de la Ciencia:
- Biología Estructural Biología estructural.
- Biología Molecular Biología Molecular
- La bioquímica es la bioquímica.
Sus antecedentes:
- Gsalpha es una subunidad alfa de la proteína G heterotrimérica crucial que activa la adenilil ciclasa.
- Pertenece a una familia de proteínas de unión a GTP que regulan la actividad del efector de una manera dependiente de las hormonas.
Objetivo del estudio:
- Para determinar la estructura cristalina de Gsalpha en complejo con guanosina 5'-O-(3-tiotrifosfato) (GTPgammaS).
- Para comparar la estructura de Gsalpha.GTPgammaS con Gialpha.GTPgammaS para comprender la especificidad del efector.
- Para dilucidar la base molecular de la interacción entre Gsalpha y los reguladores de la señalización de la proteína G (RGS).
Principales métodos:
- Cristalografía de rayos X con una resolución de 2.5 A.
- Comparación estructural de los complejos Gsalpha.GTPgammaS y Gialpha.GTPgammaS.
- Análisis de la homología de secuencia y divergencia estructural entre Gsalpha y Gialpha.
Principales resultados:
- La estructura cristalina de Gsalpha.GTPgammaS fue determinada.
- La especificidad del efector está determinada principalmente por la forma de la superficie de unión de la hélice II del interruptor y el bucle alfa3-beta5, a pesar de la alta homología de secuencia.
- La divergencia de secuencias, no las diferencias estructurales, explica la incapacidad de las proteínas RGS para estimular la actividad de la Gsalpha GTPasa.
- La superficie de unión betagamma se conserva, pero las diferencias en la hélice carboxilo-terminal y el bucle alfa4-beta6 pueden mediar la especificidad del receptor.
Conclusiones:
- Los conocimientos estructurales sobre Gsalpha proporcionan una base para comprender la especificidad de la señalización de la proteína G.
- Las diferencias en elementos estructurales específicos dictan las interacciones de efector y RGS, mientras que las regiones conservadas median la unión de la subunidad betagamma.
- Este estudio aclara cómo Gsalpha logra sus funciones específicas dentro de complejas vías de señalización celular.
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