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Estructura, función y farmacología de los GPCR de la picazón humana
Can Cao1, Hye Jin Kang1, Isha Singh2
1Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
Nature
|November 18, 2021
Resumen
Los investigadores descubrieron las estructuras de los receptores MRGPRX2 y MRGPRX4 relacionados con el picor. Este avance avanza en el desarrollo de nuevos tratamientos para el dolor, la picazón y las reacciones de hipersensibilidad.
Área de la Ciencia:
- Farmacología
- Biología estructural
- Inmunología
Sus antecedentes:
- La familia de receptores acoplados a la proteína G (MRGPRX) relacionada con Mas, incluida MRGPRX1-4, ha evolucionado recientemente.
- MRGPRX2 y MRGPRX4 son mediadores críticos de la picazón y la hipersensibilidad mediada por los mastocitos.
- MRGPRX2 señala a través de las vías Gi y Gq en los mastocitos.
Objetivo del estudio:
- Para determinar las estructuras estabilizadas por el agonista de MRGPRX2 y MRGPRX4.
- Desarrollar sondas antagonistas potentes para el MRGPRX2.
- Para facilitar el descubrimiento de fármacos guiados por la estructura para la picazón e hipersensibilidad.
Principales métodos:
- Se determinaron las estructuras del complejo ternario de MRGPRX2 con Gi1 y Gq utilizando cortistatina-14 y un agonista sintético.
- Desarrolló potentes sondas antagonistas dirigidas a MRGPRX2.
- Caracterizó un agonista específico de MRGPRX4 y su estructura compleja con Gq.
Principales resultados:
- Se proporcionan estructuras estabilizadas por agonistas para MRGPRX2 en complejo con Gi1 y Gq.
- Se identificó un agonista específico para MRGPRX4 y su complejo estructural con Gq.
- Desarrolló nuevas sondas antagonistas de MRGPRX2.
Conclusiones:
- Conocimientos estructurales sobre los mecanismos de activación de MRGPRX2 y MRGPRX4.
- Los hallazgos allanan el camino para el desarrollo terapéutico específico.
- Acelera el descubrimiento de agentes para tratar el dolor, la picazón y la hipersensibilidad.
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