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La inactivación del receptor acoplado a la proteína G por un anticuerpo alostérico agonista inverso

Tomoya Hino¹, Takatoshi Arakawa, Hiroko Iwanari

¹Iwata Human Receptor Crystallography Project, ERATO, Japan Science and Technology Agency, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.

|January 31, 2012

Resumen

Los investigadores desarrollaron un nuevo anticuerpo que se une al receptor de adenosina A2A (A2A) AR, bloqueándolo en un estado inactivo. Este descubrimiento ofrece un nuevo método para modular la actividad del receptor acoplado a la proteína G.

Área de la Ciencia:

La bioquímica es la bioquímica.
Biología Estructural Biología estructural.
Farmacología Farmacología.

Sus antecedentes:

Los receptores acoplados a la proteína G (GPCR) son proteínas cruciales de la superficie celular que median las respuestas celulares.
El receptor de adenosina A(2A) (A(2A) AR) juega un papel clave en la función cardiovascular y la liberación de neurotransmisores.

Objetivo del estudio:

Para generar un anticuerpo monoclonal dirigido a la A(2A) AR humana.
Para dilucidar la base estructural de la interacción de anticuerpos con A(2A) AR.
Explorar una nueva estrategia para la modulación de GPCR.

Principales métodos:

Generación de un anticuerpo monoclonal de ratón contra el humano A(2A) AR.
Cristalografía de rayos X para determinar la estructura de A(2A) AR en complejo con el fragmento de anticuerpo Fab (Fab2838).

Principales resultados:

El anticuerpo Fab2838 se une a la superficie intracelular de A(2A) AR.
La región CDR-H3 del anticuerpo interactúa con el receptor, imitando el sitio de unión a la proteína G.
Fab2838 estabiliza A(2A) AR en una conformación inactiva, evitando la unión del agonista.

Conclusiones:

Se ha desarrollado un nuevo anticuerpo (Fab2838) que inhibe alostéricamente A(2A) AR.
El mecanismo del anticuerpo proporciona información sobre la regulación de la GPCR.
Este enfoque representa una nueva estrategia para modular la actividad de GPCR.

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