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Estructura de un GPCR metabotrópico receptor de glutamato 1 de clase C unido a un modulador alostérico

Huixian Wu¹, Chong Wang, Karen J Gregory

¹Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

Science (New York, N.Y.)

|March 8, 2014

Resumen

Los investigadores aclararon la estructura del receptor metabotrópico humano de glutamato 1 (mGlu1) unido a un modulador. Esto revela conocimientos sobre la modulación alostérica y los mecanismos de activación de los receptores acoplados a proteínas G de clase C (GPCR).

Área de la Ciencia:

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

Sus antecedentes:

Los receptores metabotrópicos de glutamato (mGluR) son receptores acoplados a proteínas G de clase C (GPCR) cruciales para la modulación de la actividad neuronal a través del neurotransmisor excitatorio glutamato.
Comprender la estructura y función de mGluR es clave para desarrollar terapias dirigidas para trastornos neurológicos.

Objetivo del estudio:

Para determinar la estructura de alta resolución del dominio de siete transmembranas (7TM) del receptor mGlu1 humano.
Para investigar el sitio de unión de un modulador alostérico negativo (FITM) y sus implicaciones para la función del receptor.
Esclarecer los mecanismos de modulación y activación alosterica de los GPCR de clase C.

Principales métodos:

Se empleó cristalografía de rayos X para determinar la estructura 3D del dominio 7TM del receptor mGlu1 unido al FITM a una resolución de 2,8 angstroms.
Se utilizaron estudios de relación estructura-actividad, mutagenesis y modelado de dímeros de longitud completa para comprender la dinámica e interacciones de los receptores.
Se identificó la dimerización 7TM paralela mediada por el colesterol como un posible mecanismo de señalización.

Principales resultados:

La estructura reveló un sitio único de unión del modulador dentro del dominio 7TM del receptor mGlu1, parcialmente superpuesto pero más restringido que los GPCR de clase A.
Se observó que el colesterol mediaba un dímero 7TM paralelo, lo que sugiere un papel en la transmisión de señales desde el dominio extracelular.
Se obtuvieron ideas sobre cómo la unión del glutamato al dominio extracelular puede transmitirse a través de las interacciones 7TM.

Conclusiones:

La estructura determinada proporciona una base molecular para la comprensión de la modulación alostérica de los receptores mGlu1.
Los hallazgos destacan la importancia de las interacciones del dominio 7TM y el colesterol en la activación y señalización de los GPCR de clase C.
Este estudio ofrece información valiosa para el diseño racional de nuevos fármacos dirigidos a mGluRs.

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