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La estructura del canal iónico TRPA1 sugiere mecanismos reguladores
Candice E Paulsen1, Jean-Paul Armache2, Yuan Gao3
1Department of Physiology, University of California, San Francisco, California 94158-2517, USA.
Nature
|April 10, 2015
Resumen
El canal iónico TRPA1, un sensor de irritantes ambientales, ha tenido su estructura revelada. Este avance proporciona un plan para diseñar nuevos medicamentos para aliviar el dolor y la inflamación.
Área de la Ciencia:
- Biología molecular La biología molecular.
- Biología estructural Biología estructural.
- La biofísica es la biofísica.
Sus antecedentes:
- El canal iónico TRPA1, o receptor del wasabi, detecta los irritantes ambientales y los compuestos endógenos.
- Los antagonistas de TRPA1 son prometedores para el tratamiento de afecciones inflamatorias relacionadas con la exposición a irritantes.
- Comprender los mecanismos estructurales de TRPA1 es crucial para el desarrollo terapéutico, pero sigue siendo en gran medida desconocido.
Objetivo del estudio:
- Para aclarar los mecanismos estructurales que rigen la regulación del canal TRPA1.
- Para determinar la estructura de alta resolución de TRPA humano de cuerpo entero1.1.
- Proporcionar una base estructural para el diseño de nuevas terapias dirigidas a TRPA1.
Principales métodos:
- Se empleó la crio-microscopía electrónica de una sola partícula (cryo-EM).
- La estructura del TRPA1 humano de cuerpo entero se determinó con una resolución de aproximadamente 4 Å.
- Los experimentos se llevaron a cabo en presencia de farmacóforos, incluyendo un potente antagonista.
Principales resultados:
- El estudio reveló características estructurales inesperadas del canal TRPA1.
- Se identificó un extenso dominio de ensamblaje de bobina en espiral, estabilizado por cofactores de polifosfato.
- Se observó un nexo altamente integrado que converge en un dominio alostérico similar a TRP.
Conclusiones:
- La estructura determinada ofrece nuevos conocimientos sobre los mecanismos de regulación del canal TRPA1.
- Los hallazgos establecen un plan estructural para el diseño racional de agentes analgésicos y antiinflamatorios.
- Este trabajo avanza el potencial para el desarrollo de terapias dirigidas basadas en TRPA1.
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