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La activación y la modulación alostérica de un receptor de acetilcolina muscarínica

Andrew C Kruse¹, Aaron M Ring, Aashish Manglik

¹1] Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA [2].

|November 22, 2013

Resumen

Los investigadores determinaron la estructura activa del receptor de acetilcolina muscarínico M2 (M2R). Esto revela cambios conformacionales significativos y conocimientos sobre la modulación alostérica, avanzando en la comprensión del receptor acoplado a la proteína G (GPCR).

Área de la Ciencia:

Biología estructural Biología estructural.
Farmacología molecular farmacología molecular.
La bioquímica es la bioquímica.

Sus antecedentes:

Los receptores acoplados a la proteína G (GPCR) son objetivos farmacológicos cruciales, pero sus mecanismos de activación siguen siendo poco conocidos.
Existen estructuras de estado activo limitadas, principalmente para el receptor adrenérgico β2 (β2AR) y la rodopsina.

Objetivo del estudio:

Para dilucidar el mecanismo de activación del receptor humano de acetilcolina muscarínica M2 (M2R).
Investigar las bases estructurales de la modulación alostérica de M2R.

Principales métodos:

Cristalografía de rayos X de M2R. ligado al agonista.
Estabilización del estado activo utilizando un fragmento de anticuerpo camélido mimético de proteína G.
Aislamiento a través de la visualización de la superficie de la levadura y la selección conformacional.
Co-cristalización con un agonista ortostérico y un modulador alostérico positivo.

Principales resultados:

Se informó de la primera estructura de estado activo ligada al agonista de M2R. humano.
Se observaron extensos cambios conformacionales en las regiones extracelulares y el sitio ortostérico, que exceden los de β2AR y rodopsina.
Se caracteriza por la unión de un modulador alostérico positivo (LY2119620) a un sitio preformado, induciendo una pequeña contracción de bolsillo.

Conclusiones:

La activación de la M2R implica cambios conformacionales extracelulares significativos.
La modulación alostérica por LY2119620 ocurre en un sitio distinto dentro del vestíbulo extracelular.
Estos hallazgos proporcionan información crítica sobre la activación de M2R y la modulación alostérica para el descubrimiento de fármacos GPCR.

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