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Estructura cristalina del receptor GLP-1 unido a un agonista del péptido

Ali Jazayeri¹, Mathieu Rappas¹, Alastair J H Brown¹

¹Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, UK.

|June 1, 2017

Resumen

Los investigadores determinaron la estructura cristalina del receptor de péptido similar al glucagón 1 (GLP-1) unido a un agonista del péptido. Esta visión estructural guió el diseño de nuevos agonistas peptídicos con actividad potente para el tratamiento de la diabetes.

Área de la Ciencia:

La bioquímica
Biología estructural
Farmacología

Sus antecedentes:

El péptido parecido al glucagón 1 (GLP-1) es crucial para la homeostasis de la glucosa a través de la regulación de la insulina.
Los agonistas del péptido GLP-1 son tratamientos efectivos para la diabetes.
Comprender el mecanismo molecular de acción de GLP-1 es clave para el desarrollo de fármacos.

Objetivo del estudio:

Para aclarar el mecanismo molecular de la acción del péptido GLP-1.
Determinar la estructura cristalina del receptor GLP-1 de longitud completa unido a un agonista peptídico truncado.

Principales métodos:

Se utilizó la cristalografía de rayos X para determinar la estructura del complejo GLP- 1 receptor- péptido.
Diseño guiado por la estructura de nuevos agonistas peptídicos.

Principales resultados:

La estructura cristalina reveló que el agonista peptídico adopta una conformación alfa helicoidal dentro de la bolsa de unión al receptor.
La disposición de la hélice transmembrana indicó una conformación activa del receptor.
Los agonistas peptídicos diseñados demostraron una potente actividad in vivo en un modelo de ratón con diabetes.

Conclusiones:

La estructura determinada proporciona información molecular sobre la activación del receptor GLP-1.
La información estructural es valiosa para diseñar terapias mejoradas basadas en GLP-1.
Este trabajo facilita el desarrollo de nuevos tratamientos para la diabetes.

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