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El paisaje energético y alostérico para la inhibición de KRAS
Chenchun Weng1, Andre J Faure1, Albert Escobedo1
1Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
Nature
|December 18, 2023
Resumen
Los investigadores mapearon la comunicación alostérica en KRAS, identificando sitios farmacológicos mediante el análisis de miles de mutaciones. Este enfoque revela nuevas dianas terapéuticas para las enfermedades al comprender cómo las mutaciones afectan las interacciones de las proteínas.
Área de la Ciencia:
- Bioquímica y Biología Estructural
- Genómica y Proteómica
- Descubrimiento y desarrollo de fármacos
Sus antecedentes:
- Muchos objetivos terapéuticos de proteínas son "indruggables" debido a las dificultades para inhibir directamente las interacciones proteína-proteína.
- La identificación de sitios alostéricos, que modulan la actividad de las proteínas indirectamente, es crucial para apuntar a dichas proteínas, pero faltan mapas completos.
Objetivo del estudio:
- Para crear atlas globales de la comunicación alostérica inhibidora en el KRAS.
- Identificar y validar los sitios alostéricos en el KRAS para la orientación terapéutica.
Principales métodos:
- Efectos cuantificados de más de 26,000 mutaciones KRAS en el plegamiento de proteínas y la unión a seis parejas.
- Interacciones genéticas utilizadas en mutantes dobles para mediciones biofísicas a gran escala.
- Inferido más de 22,000 cambios de energía libre causal para mapear los efectos alostéricos.
Principales resultados:
- Paisajes energéticos desarrollados que cuantifican los cambios inducidos por la mutación en la especificidad de unión de KRAS.
- Se identificaron múltiples bolsas superficiales alostericamente activas, incluyendo una bolsa distal en el lóbulo C-terminal.
- Se ha demostrado que las mutaciones alostéricas pueden inhibir o alterar la especificidad de unión a los efectores.
Conclusiones:
- El estudio proporciona un mapa completo de la comunicación alostérica inhibidora en el KRAS.
- Se han validado múltiples sitios alostéricos con potencial terapéutico para modular la activación de la vía.
- La metodología puede aplicarse ampliamente para identificar dianas alostéricas en otras proteínas.
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