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Estructuras del canal Nav1.7 humano en complejo con subunidades auxiliares y toxinas animales
Huaizong Shen1,2,3, Dongliang Liu1,2,3, Kun Wu4
1State Key Laboratory of Membrane Biology, Tsinghua University, Beijing 100084, China.
Science (New York, N.Y.)
|February 16, 2019
Resumen
Los conocimientos estructurales sobre el canal de sodio controlado por voltaje Nav1.7, un objetivo clave para el alivio del dolor, se revelaron utilizando microscopía criolectrónica. Estos hallazgos allanan el camino para el desarrollo de nuevos analgésicos.
Área de la Ciencia:
- Biología estructural
- La neurociencia
- Farmacología
Sus antecedentes:
- El canal de sodio controlado por voltaje Nav1.7 es un objetivo crítico para el desarrollo de nuevas terapias para aliviar el dolor.
- Comprender la estructura del canal es esencial para diseñar analgésicos efectivos.
Objetivo del estudio:
- Determinar las estructuras de microscopía criolectrónica del complejo humano Nav1.7-β1-β2 unido a los bloqueadores de poros y a las toxinas modificadoras de la entrada (GMT).
- Para aclarar la base estructural de la función y la inhibición de Nav1.7.
Principales métodos:
- Para determinar las estructuras se utilizó la crio-microscopía electrónica (crio-EM).
- El estudio utilizó dos combinaciones de bloqueadores de poros y GMT: tetrodotoxina con protoxina-II, y saxitoxina con huwentoxina-IV.
Principales resultados:
- Se obtuvieron estructuras de alta resolución (3.2 angstroms) del complejo Nav1.7.
- Las estructuras revelaron conformaciones casi idénticas con cambios menores en el dominio II sensible al voltaje (VSDII) y los sitios de unión de toxinas.
- Las estructuras observadas pueden representar un estado inactivado del canal.
Conclusiones:
- Las estructuras determinadas proporcionan información sin precedentes sobre la función y la inhibición del canal Nav1.7.
- Estos hallazgos sientan las bases para el desarrollo de fármacos estructuralmente asistidos dirigidos a Nav1.7 para el control del dolor.
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