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Estructura de un receptor de serotonina acoplado a Gq y alucinógeno

Kuglae Kim¹, Tao Che¹, Ouliana Panova²

¹Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599-7365, USA.

|September 18, 2020

Resumen

Se revelan conocimientos estructurales sobre cómo los alucinógenos como el LSD y la psilocibina activan el receptor de serotonina 5-HT2A (HTR2A). Comprender estos mecanismos moleculares es clave para desarrollar nuevas terapias para los trastornos neuropsiquiátricos.

Área de la Ciencia:

La neurociencia
Farmacología
Biología estructural

Sus antecedentes:

Los psicodélicos, incluida la dietilamida de ácido lisérgico (LSD) y la psilocibina, son conocidos por su uso recreativo y su potencial terapéutico emergente en trastornos neuropsiquiátricos.
El receptor de serotonina 5-HT2A (HTR2A) es un objetivo crítico tanto para los efectos terapéuticos como para los alucinógenos de los psicodélicos.
Los mecanismos moleculares precisos que subyacen a la acción psicodélica en el HTR2A siguen siendo incompletamente entendidos.

Objetivo del estudio:

Para aclarar la base molecular de la acción psicodélica de las drogas en el HTR2A.
Para determinar la estructura del estado activo de HTR2A en complejo con un alucinógeno y una proteína G.
Comparar las estructuras de HTR2A unidas a diferentes ligandos para comprender la activación y la señalización.

Principales métodos:

Se utilizó la crio-microscopía electrónica (cryo-EM) para determinar la estructura de HTR2A unido al 25-CN-NBOH y un heterotrimero Gαq.
Se empleó la cristalografía de rayos X para obtener estructuras de HTR2A complejas con LSD (un ligando sesgado por arrestina) y metiotepina (un agonista inverso).

Principales resultados:

Se determinó la estructura del estado activo de HTR2A unido al alucinógeno 25-CN-NBOH en complejo con Gαq.
Las comparaciones estructurales revelaron interacciones clave y cambios conformacionales involucrados en la activación de HTR2A.
Las diferencias en las estructuras resaltan los determinantes del acoplamiento de la proteína G frente a la arrestina.

Conclusiones:

Estos hallazgos estructurales proporcionan información molecular sobre cómo los psicodélicos activan el HTR2A.
La comprensión de estas interacciones puede guiar el diseño de terapias novedosas y selectivas para afecciones neuropsiquiátricas.
El estudio acelera el descubrimiento de fármacos dirigidos al HTR2A para aplicaciones terapéuticas.

Palabras clave:

GPCR y sus derivados El LSD Psicodélico El receptor de la serotonina Transducción de señales Biología estructural

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