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La unión de moléculas pequeñas a la ranura menor del ADN está mediada por un grupo de agua conservada
DengGuo Wei1, W David Wilson, Stephen Neidle
1UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, United Kingdom.
Journal of the American Chemical Society
|January 2, 2013
Resumen
Un grupo de agua conservado en ranuras menores de ADN estabiliza la unión de moléculas pequeñas. Esta red de hidratación, distinta de la columna vertebral de la hidratación, es crucial para el posicionamiento de los ligandos y explica las afinidades de unión.
Área de la Ciencia:
- Biología Estructural Biología estructural.
- La bioquímica es la bioquímica.
- La biofísica molecular es la biofísica molecular.
Sus antecedentes:
- El surco menor del ADN es un sitio de unión clave para moléculas pequeñas, incluidos los agentes terapéuticos.
- Comprender el papel del agua en las interacciones ADN-ligando es crucial para el diseño de fármacos.
- Estudios anteriores identificaron una "columna vertebral de la hidratación" en el surco menor del ADN-B.
Objetivo del estudio:
- Para dilucidar el papel estructural de las moléculas de agua en la complejidad del ADN con ligandos de unión de ranura menor.
- Para caracterizar un grupo de agua conservada en las regiones ricas en A/T de la ranura menor del ADN.
- Para correlacionar la estructura de los grupos de agua con las afinidades de unión de ligandos y la termodinámica.
Principales métodos:
- Cristalografía de rayos X de alta resolución de complejos de ligando de ADN.
- Análisis estructural de las redes de agua dentro de la ranura menor del ADN.
- Comparación de las estructuras de ADN nativas con los estados ligand-unidos.
Principales resultados:
- Se identificó un grupo conservado de 11 moléculas de agua vinculadas en estructuras de ADN nativas y ligandos.
- Este grupo de agua se encuentra en la ampliación de la región rica en A / T de la ranura menor.
- El grupo de agua forma extensos enlaces de hidrógeno con fosfatos de la columna vertebral del ADN y ligandos unidos, estabilizando la unión del ligando.
- El grupo de agua identificado es distinto de, pero vinculado a, la columna vertebral de la hidratación, que es desplazada por ligandos.
Conclusiones:
- Un nuevo grupo de agua juega un papel estructural crítico en la estabilización de moléculas pequeñas no unidas covalentemente en la ranura menor del ADN-B.
- Esta red de hidratación media las interacciones entre el ADN y los ligandos, influyendo en la afinidad de unión y la termodinámica.
- Los hallazgos proporcionan información sobre los mecanismos moleculares de reconocimiento de ligandos de ADN y ofrecen una base para el diseño racional de fármacos dirigidos a sitios de ADN ricos en AT.
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