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Descubrimiento de sistemas de señalización humana: emparejamiento de péptidos con receptores acoplados a proteínas G
Simon R Foster1, Alexander S Hauser1, Line Vedel1
1Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Cell
|November 2, 2019
Resumen
Los investigadores identificaron nuevas conexiones entre los péptidos y los receptores acoplados a proteínas G (GPCR), ampliando nuestra comprensión de los sistemas de señalización humanos. Este descubrimiento allana el camino para futuras investigaciones sobre su papel en la salud y la enfermedad.
Área de la Ciencia:
- Fisiología humana y señalización molecular
- La genómica y la bioinformática
- Descubrimiento de fármacos y farmacología de receptores
Sus antecedentes:
- El sistema peptídico, una vasta red de interacciones ligando-receptor, sigue siendo incompletamente entendido, con muchos péptidos y receptores acoplados a proteínas G (GPCR) que carecen de funciones fisiológicas definidas.
- Más de 100 receptores acoplados a proteínas G (GPCR) y numerosos péptidos tienen funciones desconocidas, lo que dificulta la comprensión integral de las vías de señalización humanas.
Objetivo del estudio:
- Para emparejar sistemáticamente los péptidos afines con sus correspondientes receptores acoplados a proteínas G (GPCR).
- Identificar nuevos sistemas de señalización peptídica y ampliar la red conocida de péptidos GPCR.
- Descubrir posibles objetivos terapéuticos mediante la vinculación de los GPCR huérfanos con trastornos asociados a la enfermedad.
Principales métodos:
- Genómica comparativa entre 313 especies para identificar las características de señalización conservadas.
- Análisis bioinformático de las secuencias y estructuras humanas de GPCR de clase A.
- Tres ensayos bioquímicos ortogonales para validar los emparejamientos péptido-receptor.
Principales resultados:
- Se emparejó con éxito 17 ligandos endógenos propuestos con cinco receptores huérfanos acoplados a proteínas G (GPCR) relacionados con trastornos genéticos, neoplásicos, nerviosos y del sistema reproductivo.
- Se identificaron péptidos adicionales para nueve receptores acoplados a proteínas G (GPCR) con ligandos conocidos y relevancia fisiopatológica.
- Características universales descubiertas que indican posibles sistemas de señalización peptídica adicionales.
Conclusiones:
- Este enfoque computacional y experimental integrado expande significativamente la red conocida de péptidos GPCR humanos.
- Los hallazgos proporcionan una base para aclarar las funciones de los sistemas de señalización recién identificados en la fisiología y la enfermedad humanas.
- Abre nuevas vías para intervenciones terapéuticas dirigidas a vías peptidérgicas previamente no caracterizadas.
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