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Estructura del receptor δ-opioide unido al naltrindole

Sébastien Granier¹, Aashish Manglik, Andrew C Kruse

¹Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA. granier@stanford.edu

|May 19, 2012

Resumen

La estructura cristalina del receptor delta-opioide del ratón (δ-OR) revela regiones conservadas y divergentes en su bolsillo de unión. Este hallazgo explica cómo los receptores opioides logran la selectividad de los ligandos y valida el modelo de dirección de mensaje.

Área de la Ciencia:

Biología estructural Biología estructural.
Neurofarmacología y Neurofarmacología.
Los receptores acoplados a la proteína G (GPCR)

Sus antecedentes:

Los receptores opioides (μ, δ, κ) son GPCR dirigidos para el control del dolor.
El receptor delta-opioide (δ-OR) está involucrado en la analgesia y otras funciones neurológicas.
Existen datos estructurales recientes para μ-OR y κ-OR, pero no para δ-OR.

Objetivo del estudio:

Para determinar la estructura cristalina del ratón δ-OR unido al naltrindole.
Comprender los mecanismos de reconocimiento de ligandos conservados y selectivos por subtipo en los receptores de opioides.
Proporcionar conocimientos estructurales sobre el modelo de direcciones de mensajes de la farmacología de los receptores de opioides.

Principales métodos:

Cristalografía de rayos X para obtener la estructura cristalina del ratón δ-OR.
Comparación estructural con las estructuras μ-OR y κ-OR.
Análisis de las interacciones de la bolsa de unión δ-OR y los ligandos.

Principales resultados:

Se determinó la estructura cristalina del ratón δ-OR.
El bolsillo de unión δ-OR ha conservado regiones superiores inferiores y divergentes.
Estas regiones explican el reconocimiento conservado de opioides y la selectividad de subtipos.

Conclusiones:

La estructura δ-OR aclara el reconocimiento de ligandos conservados y los mecanismos de selectividad de subtipos.
Los hallazgos validan estructuralmente el modelo de dirección de mensaje de la farmacología de los opioides.
La organización estructural observada puede ser común en otras familias de GPCR.

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