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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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Activación conservada de la GPCR de clase B por un agonista intracelular sesgado
Li-Hua Zhao1,2, Qian He3,4, Qingning Yuan3
1State Key Laboratory of Drug Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. zhaolihuawendy@simm.ac.cn.
Nature
|July 31, 2023
Resumen
Los investigadores descubrieron un nuevo sitio de unión para los fármacos de molécula pequeña dirigidos al receptor de la hormona paratiroidea 1 (PTH1R). Este hallazgo podría conducir a medicamentos disponibles por vía oral para los receptores acoplados a proteínas G de clase B (GPCR).
Área de la Ciencia:
- La bioquímica
- Biología estructural
- Farmacología
Sus antecedentes:
- Los receptores acoplados a proteínas G de la clase B (GPCR), como GLP1R y PTH1R, son objetivos farmacológicos cruciales.
- Si bien existen medicamentos peptídicos, los medicamentos de moléculas pequeñas disponibles por vía oral para estos receptores aún están en desarrollo.
Objetivo del estudio:
- Determinar la estructura de alta resolución del PTH1R humano unido a una proteína G y a un agonista de molécula pequeña.
- Aclarar el modo de unión del agonista de moléculas pequeñas PCO371 y sus implicaciones para el diseño de fármacos.
Principales métodos:
- Análisis estructural de alta resolución de PTH1R humano complejado con Gs y PCO371.
- Ensayos funcionales para evaluar la actividad agonista y el sesgo de señalización de PCO371.
- Estudios de mutagenesis dirigidos al sitio en PTH2R y GLP1R para investigar la conservación de la unión a PCO371.
Principales resultados:
- Se identificó un nuevo sitio de unión para el agonista de molécula pequeña PCO371 en la interfaz citoplasmática de PTH1R con Gs.
- Este sitio de unión difiere significativamente de los sitios de unión de ligandos de GPCR conocidos anteriormente.
- PCO371 actúa como un agonista sesgado por la proteína G, activando selectivamente la señalización Gs sobre la señalización arrestina.
- Los residuos conservados en la bolsa de unión PCO371 sugieren la posibilidad de atacar otros GPCR de clase B.
Conclusiones:
- El descubrimiento de un sitio de unión PCO371 distinto en PTH1R abre nuevas vías para el diseño de agonistas de moléculas pequeñas disponibles por vía oral.
- Este hallazgo facilita el desarrollo de agonistas sesgados que modulan selectivamente la señalización de la proteína G, lo que podría conducir a mejores terapias.
- La naturaleza conservada de la bolsa vinculante ofrece una estrategia prometedora para dirigir una gama más amplia de GPCR de clase B.
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