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Análisis de simulación de dinámica molecular de la activación inicial de JAK1: Dinámica conformacional inducida por

Xinyu Peng¹, Kefu Liu¹, Guodong Chen²

¹Department of Biomedical Informatic, School of Life Sciences, Central South University, Changsha 410083, China.

Life (Basel, Switzerland)

|August 28, 2025

Resumen

La fosforilación de la Janus quinasa 1 (JAK1) en los residuos de tirosina Y1034 y Y1035 promueve su apertura. La bifosforilación, especialmente en Y1035, es clave para la activación de JAK1, ofreciendo información sobre la intervención de la enfermedad.

Área de la Ciencia:

La bioquímica
Biología molecular
Biología estructural

Sus antecedentes:

La Janus quinasa (JAK) es crucial para la señalización de citoquinas.
La hiperactividad de JAK conduce a varias enfermedades.
El mecanismo de activación preciso de JAK1 sigue siendo elusivo.

Objetivo del estudio:

Investigar el papel de los residuos de tirosina Y1034 y Y1035 en la activación de JAK1.
Para aclarar los mecanismos moleculares de los cambios conformacionales JAK1.
Proporcionar conocimientos para la orientación terapéutica de JAK1.

Principales métodos:

Se utilizaron simulaciones de dinámica molecular.
Las transiciones conformacionales analizadas del dominio de la tirosina quinasa (TK) JAK1.
Investigó el impacto de la fosforilación en Y1034 y Y1035.

Principales resultados:

La bifosforilación en Y1034 y Y1035 promueve la transición a la conformación abierta de JAK1.
pY1035 tiene un papel más importante que pY1034 en la promoción de la apertura.
La fosforilación aumenta la carga superficial negativa, ayudando a la disociación del dominio TK-FERM.
Los enlaces de hidrógeno estables en una región de bucle impiden parcialmente la activación completa.

Conclusiones:

La fosforilación de Y1034 y Y1035 es crítica para la activación inicial de JAK1.
pY1035 juega un papel dominante en el cambio conformacional al estado abierto.
La comprensión de estos mecanismos puede informar estrategias para el tratamiento de enfermedades relacionadas con JAK1.

Palabras clave:

Delphi también.JAK (en inglés)Activación del JAK electrostático Simulaciones dinámicas moleculares Fosforilación de la tirosina

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