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Conocimientos estructurales sobre el reconocimiento de ligandos por el receptor de ácido lisofosfatídico LPA
Reiya Taniguchi1,2, Asuka Inoue3,4, Misa Sayama5
1Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
Nature
|August 10, 2017
Resumen
La estructura cristalina del receptor del ácido lisofosfatídico 6 (LPA6) revela su mecanismo único de unión al ligando. Este hallazgo aclara cómo los receptores LPA no EDG reconocen los ligandos, cruciales para comprender sus roles en las enfermedades.
Área de la Ciencia:
- Biología estructural
- Farmacología molecular
- La bioquímica
Sus antecedentes:
- La señalización del ácido lisofosfatídico (LPA) involucra seis receptores acoplados a la proteína G, implicados en el cáncer y la fibrosis, lo que los convierte en posibles objetivos farmacológicos.
- Las estructuras de la familia de genes de diferenciación endotelial (EDG) (LPA1-3) son conocidas, pero la familia no EDG (LPA4-6) sigue siendo poco conocida debido a la falta de datos estructurales.
- Comprender los mecanismos de los receptores de LPA es vital, especialmente para la familia no EDG, que incluye LPA6, vinculada a la pérdida de cabello congénita.
Objetivo del estudio:
- Determinar la estructura cristalina del receptor del ácido lisofosfatídico 6 (LPA6).
- Para aclarar el mecanismo de reconocimiento de ligandos de la familia no EDG de receptores LPA.
- Proporcionar información estructural sobre la función de LPA6 y el desarrollo potencial de fármacos.
Principales métodos:
- Cristalografía de rayos X de LPA6 con una resolución de 3,2 Å.
- Análisis de la unión de ligandos y estudios de acoplamiento.
- Mutagénesis dirigida al sitio para investigar las interacciones de residuos.
Principales resultados:
- La estructura cristalina de LPA6 reveló una bolsa de unión de ligando lateralmente abierta que acomoda la cadena acil de LPA.
- Se identificaron residuos conservados cargados positivamente en la cavidad central como clave para la unión del grupo fosfato LPA.
- Los análisis de mutagenesis y acoplamiento sugirieron que la activación del receptor implica un desplazamiento conformacional de las hélices transmembrana 6 y 7.
Conclusiones:
- El estudio aclara el modo distinto de unión de ligandos de LPA6, diferenciándolo de otros receptores de LPA.
- Los hallazgos proporcionan una base estructural para comprender la activación de los receptores LPA no EDG.
- Esta información estructural es crucial para el diseño racional de terapias dirigidas para enfermedades que implican la señalización de LPA.
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