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Bases estructurales para el bloqueo de la corriente de los poros en parálisis periódica
Daohua Jiang1, Tamer M Gamal El-Din1, Christopher Ing2,3
1Department of Pharmacology, University of Washington, Seattle, WA, USA.
Nature
|May 18, 2018
Resumen
Las mutaciones en los canales iónicos causan parálisis periódica al crear fugas. Los estudios estructurales revelan mecanismos atómicos, identificando objetivos farmacológicos para el tratamiento de la debilidad muscular en estas enfermedades hereditarias.
Área de la Ciencia:
- Biología molecular
- La biofísica
- La genética
Sus antecedentes:
- La parálisis periódica incluye enfermedades hereditarias del músculo esquelético que causan debilidad muscular episódica.
- Estas condiciones se derivan de mutaciones en los canales de sodio (Nav1.4) o de calcio (Cav1.1) regulados por voltaje.
- Las mutaciones específicas en las cargas de entrada (R1-R3) conducen a formas hipocalémicas o normocalémicas debido a la fuga de cationes.
Objetivo del estudio:
- Para aclarar los mecanismos a nivel atómico de la parálisis periódica.
- Investigar la base estructural de la fuga de cationes en los canales de iones regulados por voltaje.
- Identificar posibles objetivos farmacológicos para la intervención terapéutica.
Principales métodos:
- Análisis estructural de alta resolución del canal de sodio bacteriano mutante NavAb.
- Modelado molecular y simulaciones.
- Cristalografía de NavAb(R2G) en complejo con el guanidinium.
Principales resultados:
- Las mutaciones R2G y R3G en NavAb no alteraron la estructura de la columna vertebral del sensor de tensión.
- Estas mutaciones crearon cavidades acuosas, facilitando la fuga de cationes.
- R3G habilitó una trayectoria transmembrana continua en el estado activado; R2G creó una en el estado de reposo.
- Los sitios de unión de guanidinium en NavAb(R2G) sugieren un objetivo de la droga.
Conclusiones:
- Los conocimientos estructurales sobre la formación de poros de entrada aclaran la patogénesis de la parálisis periódica.
- Los hallazgos revelan mecanismos a nivel atómico de la disfunción del canal iónico.
- Se identificaron posibles objetivos farmacológicos para el alivio sintomático de la parálisis periódica.
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