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Estructura cryo-EM del complejo de señalización del receptor cannabinoide humano CB2-G_i

Changrui Xing¹, Youwen Zhuang², Ting-Hai Xu³

¹Department of Pharmaceutical Sciences, Computational Chemical Genomics Screen Center, School of Pharmacy, and NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA 15261, USA; Drug Discovery Institute and Departments of Computational Biology and of Structural Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.

|February 1, 2020

Resumen

Los investigadores descubrieron la estructura del complejo de señalización del receptor CB2, revelando cómo se unen los agonistas como WIN 55,212-2. Este descubrimiento ayuda a diseñar nuevos medicamentos para el dolor y la inflamación sin efectos secundarios CB1.

Área de la Ciencia:

Biología estructural
Neurofarmacología
La bioquímica

Sus antecedentes:

Los medicamentos para el receptor cannabinoide 2 (CB2) ofrecen un potencial terapéutico para los trastornos neurodegenerativos, la inflamación y el dolor.
Los fármacos selectivos CB2 evitan los efectos secundarios psicotrópicos asociados con la activación del receptor CB1.
La comprensión de la activación y los mecanismos de señalización CB2 es crucial para el desarrollo eficaz de fármacos.

Objetivo del estudio:

Para aclarar la base estructural de la activación del receptor CB2 y el acoplamiento de la proteína G.
Identificar los determinantes estructurales que diferencian a los agonistas CB2 de los antagonistas.
Proporcionar información sobre la función del receptor CB2 para el diseño de fármacos basado en la estructura.

Principales métodos:

Microscopía cryoelectrónica (cryo-EM) para determinar la estructura del complejo de señalización CB2-G_i humano.
Co-cristalización con el agonista WIN 55,212-2.
Acoplamiento computacional y diseño racional de nuevos agonistas y antagonistas.

Principales resultados:

Se determinó la estructura cryo-EM del complejo CB2-G_i humano unido a WIN 55,212-2.
Se identificaron las características estructurales clave que rigen la unión del ligando y la activación del receptor.
Se revelaron diferencias significativas entre CB2 y CB1 en la activación de los receptores, el reconocimiento de los ligandos y el acoplamiento G_i.

Conclusiones:

La estructura determinada proporciona una comprensión molecular de la señalización del receptor CB2.
Los conocimientos estructurales facilitan el diseño racional de agonistas y antagonistas CB2 selectivos.
Este trabajo allana el camino para el desarrollo de nuevas terapias dirigidas al sistema cannabinoide.

Palabras clave:

Estructura 3D del receptor cannabinoide CB2 Mecanismos de activación de CB2 y CB1 Complejo de señalización CB2-Gi ligado al agonista Agonista de las CB2 Especificidad del acoplamiento CB2 para Gi CB2 Descubrimiento de fármacos Agonista inverso de CB2 Estructura criogénica Acoplamiento versátil Contribución de energía residual

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