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Site Directed Spin Labeling and EPR Spectroscopic Studies of Pentameric Ligand-Gated Ion Channels
Published on: July 4, 2016
Las estructuras de rayos X de los anestésicos generales unidas a un canal iónico pentamérico ligado por ligandos
Hugues Nury1, Catherine Van Renterghem, Yun Weng
1Institut Pasteur, Groupe Récepteurs-Canaux, F-75015 Paris, France.
Nature
|January 21, 2011
Resumen
Los anestésicos generales son anestésicos generales.
Área de la Ciencia:
- La neurociencia es la neurociencia.
- Biología Estructural Biología estructural.
- La bioquímica es la bioquímica.
Sus antecedentes:
- Los anestésicos generales son ampliamente utilizados, pero sus objetivos y mecanismos moleculares siguen sin estar claros.
- Los canales iónicos ligados por pentaméricos (pLGIC), como el GABA (A) y los receptores nicotínicos de acetilcolina, son los principales objetivos.
- El canal iónico bacteriano Gloeobacter violaceus (GLIC) es un homólogo estructural sensible a los anestésicos.
Objetivo del estudio:
- Para dilucidar la base estructural de la interacción anestésico general con pLGICs.
- Para caracterizar los sitios de unión y las interacciones de propofol y desflurano con GLIC.
- Proporcionar un marco estructural para el diseño de nuevos agentes anestésicos y moduladores.
Principales métodos:
- Cristalografía de rayos X para determinar las estructuras de los complejos propofol/GLIC y desflurano/GLIC.
- Mutagénesis dirigida al sitio para investigar el papel de aminoácidos específicos en la unión y función del anestésico.
- Simulaciones de dinámica molecular para analizar la movilidad del anestésico y las interacciones dentro del sitio de unión.
Principales resultados:
- Se identificó un sitio de unión anestésico común en el dominio transmembrana superior de GLIC, preexistente en la estructura apo.
- El propofol y el desflurano exhiben modos de unión distintos dentro de este sitio, interactuando a través de las fuerzas de van der Waals.
- Las mutaciones en el sitio de unión alteraron la respuesta de protones y la farmacología anestésica de GLIC, consistentes con los datos de simulación.
Conclusiones:
- El estudio revela un sitio de unión conservado para los anestésicos generales en los pLGIC.
- Las ideas estructurales sobre la unión del propofol y el desflurano proporcionan una base para el diseño racional de fármacos.
- La comprensión de estas interacciones puede guiar el desarrollo de nuevos moduladores alostéricos para pLGIC cerebrales.
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