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Atomic Scale Structural Studies of Macromolecular Assemblies by Solid-state Nuclear Magnetic Resonance Spectroscopy
Published on: September 17, 2017
SOS-NMR: un método basado en RMN de transferencia de saturación para determinar las estructuras de los complejos
Philip J Hajduk1, Jamey C Mack, Edward T Olejniczak
1Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA. philip.hajduk@abbott.com
Journal of the American Chemical Society
|February 26, 2004
Resumen
Un nuevo método de resonancia magnética nuclear (RMN), SOS-RMN, determina las estructuras complejas ligando-proteína sin asignaciones de resonancia proteica. Este avance permite la determinación de la estructura para objetivos desafiantes, avanzando en el diseño de fármacos basados en la estructura.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
- Descubrimiento de Drogas Descubrimiento de Drogas
Sus antecedentes:
- Los métodos tradicionales como la cristalografía de rayos X y la RMN tienen limitaciones para determinar las estructuras de los complejos ligando-biomoleculares.
- Estas limitaciones son particularmente evidentes para objetivos de diferente tamaño, composición o estado oligomérico.
Objetivo del estudio:
- Introducir un nuevo método basado en RMN para el diseño de fármacos basado en la estructura.
- Para permitir la determinación de la estructura de los complejos ligando-biomoleculares independientemente de las características del objetivo.
- Para superar las limitaciones de las técnicas existentes de biología estructural.
Principales métodos:
- Utiliza la diferencia de transferencia de saturación (STD) de la espectroscopia de RMN.
- Utiliza blancos de proteínas deuteradas selectivamente para identificar la composición de aminoácidos del sitio de unión al ligando.
- El método se denomina SOS-NMR (información estructural utilizando efectos Overhauser y etiquetado selectivo).
Principales resultados:
- Determinó con éxito la estructura 3D de los complejos proteína-ligando sin requerir asignaciones de resonancia proteica.
- Valida el método en FKBP complejo con 2-(3'-piridil) -benzimidazol y MurA complejo con uridina difosfato N-acetilglucosamina.
- Amplia aplicabilidad demostrada, especialmente donde la cristalografía de rayos X y los métodos tradicionales de RMN fallan.
Conclusiones:
- SOS-NMR ofrece una poderosa alternativa para el diseño de fármacos basado en la estructura.
- El método amplía significativamente el alcance de la información estructural alcanzable para las interacciones ligando-proteína.
- Esta técnica es prometedora para las tuberías de descubrimiento de fármacos, particularmente para objetivos de proteínas difíciles de cristalizar o grandes.
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