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Estructuras de los complejos de señalización de los receptores hormonales de glicoproteína de longitud completa

Jia Duan^1,2, Peiyu Xu^1,2, Xi Cheng¹

¹The CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

|September 23, 2021

Resumen

Los conocimientos estructurales sobre la activación del receptor de la hormona luteinizante y la coriogonadotropina (LHCGR) revelan un nuevo

Área de la Ciencia:

Biología estructural
Endocrinología
Farmacología molecular

Sus antecedentes:

La hormona luteinizante (LH) y la gonadotropina coriónica (CG) son hormonas glicoproteínicas críticas para la reproducción.
Estas hormonas activan el receptor de la hormona luteinizante- coriogonadotropina (LHCGR), un receptor acoplado a la proteína G.
El LHCGR es un objetivo clave para las intervenciones terapéuticas en enfermedades endocrinas.

Objetivo del estudio:

Para aclarar los mecanismos estructurales de la activación de LHCGR por LH y CG.
Comprender el papel de una región de bisagra conservada en la señalización del receptor.
Proporcionar una base estructural para el desarrollo de nuevos fármacos dirigidos al LHCGR.

Principales métodos:

Se utilizó la criomicroscopia electrónica (cryo-EM) para determinar cuatro estructuras distintas del LHCGR.
Estructuras capturadas de tipo salvaje LHCGR en estados inactivos y activos, y un mutante constitutivamente activo.
Las estructuras complejas incluyen CG unido, la proteína Gs y un agonista alostérico (Org43553).

Principales resultados:

Se identificó un mecanismo de activación de "empujar y tirar", que involucra la unión hormonal y la dinámica del bucle bisagra.
Un fragmento de 10-residuo conservado (P10) en el bucle de bisagra actúa como un agonista atado, impulsando cambios conformacionales en el dominio transmembrana.
El agonista alostérico Org43553 estabiliza la conformación del receptor activo mediante la interacción con el fragmento P10.

Conclusiones:

Estas estructuras proporcionan un modelo unificado para la comprensión de la señalización del receptor de la hormona glicoproteína.
Los hallazgos ofrecen información crítica sobre la activación de LHCGR y la modulación alostérica.
Este trabajo sienta las bases para el descubrimiento de fármacos basados en la estructura dirigidos a los trastornos endocrinos.

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