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Estructura cristalina de un receptor lipídico acoplado a una proteína G
Michael A Hanson1, Christopher B Roth, Euijung Jo
1Receptos, 10835 Road to the Cure, San Diego, CA 92121, USA. mhanson@receptos.com
Science (New York, N.Y.)
|February 21, 2012
Resumen
La estructura cristalina del receptor de esfingosina 1-fosfato 1 (S1P(1) revela cómo se unen los antagonistas. Los ligandos acceden al receptor del receptor.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
- Farmacología Farmacología.
Sus antecedentes:
- El 1-fosfato de esfingosina (S1P) es un mediador lipídico bioactivo.
- Los receptores S1P regulan procesos fisiológicos críticos, incluido el tráfico de células inmunes y el desarrollo vascular.
- Comprender la activación del receptor S1P es clave para el desarrollo terapéutico.
Objetivo del estudio:
- Para determinar la estructura cristalina del receptor de esfingosina 1-fosfato 1 (S1P(1) unido a un antagonista.
- Para aclarar el mecanismo de acceso del ligando al bolsillo de unión S1P.
- Proporcionar información sobre el reconocimiento molecular y la activación de S1P.
Principales métodos:
- Cristalografía de rayos X de S1P(1) fusionado con T4-lizozima (S1P(1)-T4L) en complejo con un antagonista de imitación de esfingolipidos.
- Mutagénesis dirigida al sitio.
- Estudio de la relación estructura-actividad (SAR) con agonistas.
- El modelado molecular.
Principales resultados:
- La estructura cristalina revela una entrada de bolsillo de unión extracelular ocluida.
- El acceso del ligando al sitio de unión se produce lateralmente entre las hélices transmembrana I y VII.
- La estructura aclara el reconocimiento molecular y el requisito de volumen hidrofóbico en la activación de S1P.
Conclusiones:
- La estructura determinada proporciona una visión molecular detallada de la unión del antagonista S1P.
- Esto proporciona una comprensión mecanicista de cómo los ligandos acceden y activan S1P.
- Los hallazgos ayudarán en el diseño racional de los moduladores de los receptores S1P para las respuestas inmunes y de las células del estroma.
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