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Selectividad a través de la cooperatividad: estabilización preferencial de la p65/14-3-3 Interacción con productos
Madita Wolter1, Pim de Vink1, João Filipe Neves2,3
1Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Technische Universiteit Eindhoven, P.O. Box 513, Eindhoven 5600 MB, The Netherlands.
Journal of the American Chemical Society
|June 6, 2020
Resumen
Los estabilizadores sintéticos de la interacción proteína-proteína (IPP) están poco explorados. Este estudio introduce un derivado semisintético, DP-005, que estabiliza selectivamente el complejo p65/14-3-3, ofreciendo un nuevo enfoque de descubrimiento de fármacos.
Área de la Ciencia:
- La bioquímica
- Biología estructural
- Descubrimiento de drogas
Sus antecedentes:
- Los compuestos naturales pueden estabilizar las interacciones proteína-proteína (IPP), pero el diseño de estabilizadores sintéticos es limitado.
- Las proteínas 14-3-3 regulan numerosos IBP, lo que las convierte en un andamio clave para la intervención terapéutica.
- La subunidad p65 del factor de transcripción NF-κB está regulada negativamente por 14-3-3, presentando un objetivo para el control de la proliferación celular.
Objetivo del estudio:
- Explorar el uso de la cooperación en el diseño de estabilizadores sintéticos de PPI.
- Investigar la estabilización del complejo p65/14-3-3 utilizando un derivado de producto natural semisintético.
- Desarrollar un método generalizable para caracterizar y analizar la selectividad del estabilizador PPI.
Principales métodos:
- Determinación de la estructura cristalina de los complejos p65/14-3-3 en alta resolución.
- Diseño y síntesis de un derivado de producto natural semisintético (DP-005).
- Análisis de la cooperatividad para evaluar la vinculación y la selectividad del DP-005.
Principales resultados:
- Se obtuvieron dos estructuras cristalinas de alta resolución de motivos de unión 14-3-3 de p65 en complejo con 14-3-3.
- El derivado semisintético DP-005 se une a una bolsa específica en el complejo p65/14-3-3, lo que lleva a su estabilización.
- Los análisis de cooperatividad confirmaron la estabilización selectiva del complejo p65/ 14-3-3 por DP- 005 en comparación con otros IPP 14-3-3 relevantes para la enfermedad.
Conclusiones:
- Un derivado semisintético, DP-005, estabiliza selectivamente el complejo p65/14-3-3.
- Un modelo vinculante cooperativo ofrece una estrategia versátil para caracterizar y evaluar los estabilizadores de IPP.
- Este enfoque avanza en el desarrollo de fármacos sintéticos dirigidos a los IPP para aplicaciones terapéuticas.
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