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Los complejos de activador K2P2.1 (TREK-1) revelan un sitio de unión de filtro de selectividad críptico
Marco Lolicato1, Cristina Arrigoni1, Takahiro Mori2
1Cardiovascular Research Institute, University of California, San Francisco, California 941158-9001, USA.
Nature
|July 11, 2017
Resumen
Los investigadores descubrieron pequeñas moléculas que activan los canales TREK estabilizando sus
Área de la Ciencia:
- La neurociencia
- Biología estructural
- Farmacología
Sus antecedentes:
- Los canales de potasio de dominio de dos poros (K2P), particularmente la subfamilia TREK, regulan la excitabilidad neuronal y la percepción sensorial.
- Estos canales están implicados en el dolor, la sensación de temperatura y las respuestas anestésicas.
- La comprensión actual de los mecanismos de los canales K2P está limitada por la falta de herramientas farmacológicas efectivas.
Objetivo del estudio:
- Identificar y caracterizar las moléculas pequeñas que activan los canales de la subfamilia TREK.
- Para aclarar la base estructural para la activación de pequeñas moléculas de los canales K2P.
- Proporcionar nuevas sondas farmacológicas para el estudio de la función del canal K2P.
Principales métodos:
- Se utilizó la cristalografía de rayos X para determinar las estructuras de K2P2.1 (TREK-1) solo y en complejo con los activadores ML335 y ML402.
- Se realizaron ensayos electrofisiológicos funcionales para evaluar la actividad del canal en respuesta a las moléculas pequeñas.
- Se aplicaron principios de diseño de fármacos basados en la estructura para comprender las interacciones de unión.
Principales resultados:
- Se identificó una nueva clase de activadores de moléculas pequeñas (ML335 y ML402) para los canales TREK.
- Los estudios estructurales revelaron un bolsillo de unión críptico único distinto de otros sitios de canales iónicos.
- Estos activadores funcionan como cuñas moleculares, estabilizando la puerta de tipo C en un "modo de fuga" a través de interacciones catión-π.
Conclusiones:
- Se ha identificado un sitio de unión en los canales K2P que permite la estabilización de la puerta de tipo C.
- Estos hallazgos proporcionan evidencia directa para el filtrado de selectividad en los canales K2P.
- Los activadores descubiertos ofrecen herramientas valiosas para futuras investigaciones sobre la fisiología y farmacología de los canales K2P.
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