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Bases estructurales para la modulación de los canales de sodio dependientes de la tensión por toxinas animales

Huaizong Shen^1,2,3, Zhangqiang Li^1,2,3, Yan Jiang⁴

¹State Key Laboratory of Membrane Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.

Science (New York, N.Y.)

|July 28, 2018

Resumen

Las estructuras revelan cómo las toxinas animales como la tetrodotoxina (TTX) y la saxitoxina (STX) bloquean los canales de sodio (Na_v) controlados por voltaje. Esto proporciona información sobre los mecanismos de las toxinas y el posible desarrollo de nuevos fármacos para la modulación del canal Na_v.

Área de la Ciencia:

La bioquímica
Biología estructural
La neurociencia

Sus antecedentes:

Los canales de sodio regulados por voltaje (Na_v) son cruciales para la transmisión del impulso nervioso.
Las toxinas animales dirigidas a los canales Na_v se clasifican como bloqueadores de poros (por ejemplo, TTX, STX) o modificadores de entrada.
La comprensión de las interacciones entre las toxinas y los canales es clave para el desarrollo de agentes terapéuticos.

Objetivo del estudio:

Para aclarar la base estructural de la unión de la toxina a los canales Na_v.
Para visualizar la interacción del modificador de entrada Dc1a con el canal Na_vPaS.
Para detallar los mecanismos moleculares de bloqueo de los poros por TTX y STX.

Principales métodos:

Se empleó la cristalografía de rayos X para determinar estructuras de alta resolución.
Se obtuvieron estructuras para Na_vPaS unidas a Dc1a, TTX y STX.
Se utilizó la microscopía criolectrónica para lograr resoluciones de hasta 2,8 Å.

Principales resultados:

La estructura de Na_vPaS unida al modificador de entrada Dc1a se determinó con una resolución de 2,8 Å.
Las estructuras de Na_vPaS con TTX y STX se resolvieron en 2.6 Å y 3.2 Å, respectivamente.
Dc1a se une en la hendidura entre VSD_II y el poro, mientras que TTX/STX bloquea el acceso de Na⁺ al filtro de selectividad.

Conclusiones:

El estudio proporciona información a nivel atómico sobre cómo las diferentes toxinas interactúan con los canales Na_v.
Estas estructuras revelan los mecanismos precisos de bloqueo de poros por TTX y STX.
Los hallazgos facilitan el diseño basado en la estructura de nuevos moduladores de canales Na_v para fines terapéuticos.

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