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Conformaciones distintas del receptor CCK-2 asociadas con el reclutamiento de la β-arrestina-2 o la activación de la

Rémi Magnan¹, Chantal Escrieut, Véronique Gigoux

¹EA 4552, Université de Toulouse 3, 31432 Toulouse, France.

Journal of the American Chemical Society

|January 18, 2013

Resumen

Los receptores de siete transmembranas (7TMRs) adoptan estructuras distintas al unirse, lo que permite un diseño de fármacos sesgado. Este estudio revela diferencias estructurales en las conformaciones de CCK2R, cruciales para la señalización dirigida de la proteína G o la β-arrestina.

Área de la Ciencia:

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

Sus antecedentes:

Los receptores de siete transmembranas (7TMRs), o receptores acoplados a proteínas G (GPCRs), son una de las principales clases de fármacos objetivo.
Los agonistas pueden estabilizar distintas conformaciones de receptores, lo que lleva a una señalización sesgada a través de las vías de la proteína G o de la β-arrestina.
Falta evidencia estructural para distintas conformaciones del sitio de unión que inician el agonismo sesgado.

Objetivo del estudio:

Investigar las diferencias estructurales en las conformaciones CCK2R asociadas con la activación de la proteína Gq frente al reclutamiento de β-arrestin2.
Identificar los elementos estructurales responsables de la selectividad sesgada de los ligandos.

Principales métodos:

Caracterización farmacológica de las vías de activación de CCK2R.
Ensayos de inhibición competitiva con antagonistas estructuralmente distintos.
Identificación de los elementos estructurales en la cavidad de unión del ligando y del receptor.

Principales resultados:

La colecistoquinina (CCK) indujo distintas conformaciones de CCK2R (G) y CCK2R (β).
Un ligando (GV150013X) antagonizó selectivamente el CCK2R (G) pero no el CCK2R (β).
Las interacciones estructurales específicas, incluida una interacción sulfur-aromática entre las hélices transmembrana 3 y 7, fueron críticas para la estabilización de CCK2R (β).

Conclusiones:

Las distintas conformaciones estructurales de los 7TMR están asociadas con el acoplamiento de la proteína G o el reclutamiento de la β-arrestina-2.
Las ideas estructurales validan el diseño de ligandos sesgados para la orientación selectiva de los estados funcionales de 7TMR.
Este trabajo proporciona evidencia estructural para el agonismo sesgado en el receptor CCK2.

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