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Regulación específica del ligando de la superficie extracelular de un receptor acoplado a la proteína G
Michael P Bokoch1, Yaozhong Zou, Søren G F Rasmussen
1Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.
Nature
|January 8, 2010
Resumen
Diversas superficies extracelulares de receptores acoplados a proteínas G (GPCR) están acopladas conformacionalmente a sitios de unión de ligando. Dirigirse a estas superficies ofrece una nueva estrategia para el desarrollo de fármacos altamente selectivos.
Área de la Ciencia:
- Bioquímica y biología estructural.
- Farmacología Farmacología.
- Biología molecular y celular Biología molecular y celular
Sus antecedentes:
- Los receptores acoplados a la proteína G (GPCR) son proteínas transmembrana cruciales y los principales objetivos de los fármacos.
- Su superficie extracelular (ECS) es diversa, ofreciendo potencial para el descubrimiento de fármacos selectivos por subtipo.
- El papel funcional del ECS en la activación del receptor y su acoplamiento al sitio de unión sigue sin estar claro.
Objetivo del estudio:
- Para investigar los cambios conformacionales específicos del ligando en el GPCR ECS.
- Para explorar el acoplamiento funcional entre el ECS y el bolsillo de unión de ligandos ortostéricos.
- Evaluar el potencial de dirigir el ECS para el desarrollo de fármacos alostéricos.
Principales métodos:
- Se empleó la espectroscopia de resonancia magnética nuclear (RMN).
- Se investigó la dinámica conformacional del ECS del receptor adrenérgico beta (((2)).
- Se analizaron distintas conformaciones del ECS inducidas por fármacos con diferentes eficacias.
Principales resultados:
- Las diferentes eficacias de los fármacos (agonista, antagonista, agonista inverso) estabilizaron las conformaciones únicas del ECS.
- Acoplamiento conformacional directo demostrado entre el ECS y el sitio de unión ortosterica.
- Reveló comportamientos dinámicos de GPCR más allá de las estructuras cristalinas estáticas.
Conclusiones:
- El ECS GPCR está conformationally vinculado al sitio de unión orthosteric.
- Dirigirse a los diversos ECS puede producir moduladores alostéricos con alta selectividad de subtipos.
- Los estudios de RMN proporcionan nuevos conocimientos sobre la dinámica de las GPCR y los mecanismos de activación.
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