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Múltiples sitios de unión independientes para los inhibidores de moléculas pequeñas en la oncoproteína c-Myc
Dalia I Hammoudeh1, Ariele Viacava Follis, Edward V Prochownik
1Department of Chemistry, Georgetown University, Washington, District of Columbia 20057, USA.
Journal of the American Chemical Society
|May 13, 2009
Resumen
Los investigadores identificaron tres sitios de unión distintos en la oncoproteína c-Myc para los inhibidores de moléculas pequeñas. Estos sitios permiten la unión simultánea e independiente, preservando el c-Myc.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Oncología Oncología.
- Biología Estructural Biología Estructural
Sus antecedentes:
- El factor de transcripción c-Myc es frecuentemente desregulado en los cánceres, lo que lo convierte en un objetivo terapéutico clave.
- La inhibición de la dimerización de c-Myc con Max es una estrategia para bloquear su actividad oncogénica.
- El dominio básico helix-loop-helix leucine zipper (bHLHZip) de c-Myc es intrínsecamente desordenado (ID) como un monómero.
Objetivo del estudio:
- Identificar y caracterizar los sitios de unión de moléculas pequeñas en el dominio monomérico c-Myc bHLHZip.
- Investigar el mecanismo de inhibición por los conocidos inhibidores de c-Myc-Max.
- Explorar el potencial de dirigirse a proteínas intrínsecamente desordenadas para la terapia del cáncer.
Principales métodos:
- Espectroscopia de dicroísmo circular y espectroscopia de dicroísmo circular.
- Ensayos de polarización por fluorescencia en ensayos de fluorescencia.
- La espectroscopia de resonancia magnética nuclear (RMN) también se conoce como espectroscopia de resonancia magnética nuclear.
Principales resultados:
- Se identificaron tres sitios discretos de unión de moléculas pequeñas dentro del dominio c-Myc bHLHZip.
- Los siete inhibidores de Myc probados se unen a uno de estos tres sitios.
- La unión al inhibidor causa cambios conformacionales locales, pero conserva el trastorno general de la proteína e inhibe la dimerización.
- La unión a un sitio no afecta la afinidad de unión o los cambios estructurales en otros sitios, permitiendo la unión simultánea e independiente.
Conclusiones:
- El dominio c-Myc bHLHZip posee múltiples y independientes sitios de unión de pequeñas moléculas.
- Estos hallazgos apoyan un enfoque racional y genérico para inhibir las interacciones proteína-proteína que involucran proteínas intrínsecamente desordenadas al apuntar a secuencias de ID.
- Esta estrategia es prometedora para el desarrollo de nuevas terapias contra el cáncer.
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