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Estructura cristalina del receptor Frizzled 4 en un estado libre de ligandos
Shifan Yang1, Yiran Wu1, Ting-Hai Xu2
1iHuman Institute, ShanghaiTech University, Shanghai, China.
Nature
|August 24, 2018
Resumen
Los receptores rizados (FZD), cruciales para la señalización de Wnt, poseen una estructura única que dificulta la unión tradicional al ligando. Este descubrimiento puede explicar los desafíos en el desarrollo de medicamentos y sondas dirigidos a FZD.
Área de la Ciencia:
- Biología estructural
- La bioquímica
- Señalización celular
Sus antecedentes:
- Los receptores frizzled (FZD) son receptores acoplados a proteínas G de clase F (GPCR) vitales para la señalización de Wnt en organismos en desarrollo y adultos.
- Los FZD actúan como mediadores clave en la señalización Wnt, lo que los convierte en objetivos importantes para el desarrollo de fármacos y las sondas de investigación.
Objetivo del estudio:
- Determinar la estructura de resolución atómica del dominio transmembrana del receptor Frizzled 4 humano (FZD4) sin un ligando unido.
- Investigar las bases estructurales de los mecanismos de unión y activación de los ligandos en las FZD.
Principales métodos:
- Cristalografía de rayos X para obtener la estructura de resolución atómica del dominio transmembrana FZD4.
- Simulaciones de dinámica molecular en una escala de tiempo de microsegundos.
- Análisis mutacional para identificar los principales residuos y elementos estructurales implicados en la activación.
Principales resultados:
- Se reveló una arquitectura transmembrana inusual de FZD4, distinta de otras GPCR, con una hélice VI corta y apretada.
- Se identificó una bolsa de unión estrecha e hidrofílica inadecuada para los ligandos GPCR tradicionales y se encontró que se conserva en las FZD.
- Se descubrieron dos torceduras dinámicas acopladas en la hélice VII, implicadas en la activación de FZD4.
Conclusiones:
- La estructura única de FZD4 y su bolsillo de unión de ligandos presentan desafíos para el desarrollo de fármacos tradicionales.
- El bolsillo estrecho conservado a través de FZD puede explicar las dificultades en el desarrollo de ligandos específicos.
- Es probable que los FZD empleen un nuevo mecanismo de reconocimiento y activación de ligandos distinto de otros GPCR, que involucra la dinámica de la hélice VII.
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