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Análisis cristalográfico de la interacción del receptor glucocorticoide con el ADN
B F Luisi1, W X Xu, Z Otwinowski
1Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06511.
Nature
|August 8, 1991
Resumen
Los dominios de unión al ADN de los receptores de glucocorticoides se dimerizan al unirse al ADN. El espaciado del ADN determina críticamente el reconocimiento del objetivo, influyendo en las interacciones específicas y no específicas para la función del receptor de glucocorticoides.
Área de la Ciencia:
- Biología estructural Biología estructural.
- Biología molecular La biología molecular.
- Genética La genética.
Sus antecedentes:
- El receptor glucocorticoide (GR) es un receptor nuclear crucial para regular la expresión génica en respuesta a los glucocorticoides.
- El dominio de unión al ADN (DBD) de GR es responsable de reconocer y unirse a secuencias específicas de ADN, mediando la regulación transcripcional.
- Comprender la base estructural de la interacción GR-ADN es clave para descifrar su papel en varios procesos fisiológicos y patológicos.
Objetivo del estudio:
- Para dilucidar los mecanismos estructurales que subyacen a la unión de ADN al receptor de glucocorticoides.
- Para investigar cómo las variaciones en las secuencias de ADN objetivo influyen en la dimerización GR DBD y la interacción del ADN.
- Proporcionar información sobre los determinantes de especificidad de los elementos de respuesta a los glucocorticoides.
Principales métodos:
- Se empleó cristalografía de rayos X para determinar las estructuras tridimensionales del GR DBD en complejo con ADN.
- Se utilizaron dos construcciones de ADN distintas: una con una secuencia objetivo de consenso simétrico y otra con espaciado central alterado.
- El análisis estructural se centró en la interfaz de dimerización, los modos de unión al ADN y los contactos entre subunidades de ADN.
Principales resultados:
- Dos estructuras cristalinas revelaron el pliegue globular del GR DBD, con dos subestructuras nucleadas con Zn.
- Tras la unión al ADN, el GR DBD se dimeriza, con subunidades colocadas en ranuras principales adyacentes del ADN.
- La alteración del espaciado central del ADN dio lugar a la unión diferencial: una subunidad reconoció específicamente el medio sitio de consenso, mientras que la otra interactuó de manera no específica con un elemento no congénito.
Conclusiones:
- La dimerización inducida por el ADN del GR DBD es un paso crítico en el reconocimiento de objetivos.
- El espaciado preciso entre los semisitios del ADN es un determinante clave de la identidad de la secuencia objetivo y la especificidad de unión.
- Estos hallazgos ponen de relieve la intrincada interacción entre la estructura del ADN y la dimerización de proteínas en la mediación de la regulación transcripcional por el receptor de glucocorticoides.
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