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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
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Modulación alostérica y selectividad de la proteína G del receptor receptor de Ca2+
Feng He1, Cheng-Guo Wu1, Yang Gao1,2
1Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
Nature
|February 7, 2024
Resumen
La estructura del receptor sensible al calcio (CaSR) revela cómo activa las proteínas G y responde a medicamentos como el cinacalcet. Las poliaminas y el L-triptófano también modulan la actividad de CaSR a través de mecanismos distintos.
Área de la Ciencia:
- La bioquímica
- Biología estructural
- Farmacología
Sus antecedentes:
- El receptor sensible al calcio (CaSR) es un GPCR crucial para la homeostasis del calcio.
- La comprensión de los mecanismos de activación del CaSR es vital para el tratamiento de los trastornos relacionados con el calcio.
Objetivo del estudio:
- Para aclarar la base estructural de la activación del CaSR humano y su acoplamiento selectivo a las proteínas G (Gi y Gq).
- Investigar la modulación alostérica del CaSR por el cinacalcet, las poliaminas y el L-triptófano.
Principales métodos:
- Microscopía criolectrónica (crio-EM) para determinar las estructuras de alta resolución de CaSR.
- Ensayos funcionales para evaluar el acoplamiento de la proteína G y la activación del receptor.
- Investigación del CaSR en los nanodiscos de lípidos.
Principales resultados:
- La activación de CaSR por Gi y Gq implica cambios conformacionales en el dominio 7TM y las interacciones proteína-lípido.
- El acoplamiento selectivo de la proteína G está mediado por reordenamientos en los bucles intracelulares y el extremo C.
- Las poliaminas mejoran la activación de CaSR estabilizando las interacciones entre los protómeros.
- El L-triptófano y el cinacalcet se unen a sitios superpuestos dentro del haz 7TM, actuando como moduladores alostéricos.
Conclusiones:
- Proporciona un marco estructural para la activación y la selectividad de la proteína G de CaSR.
- Revela distintos sitios de unión y mecanismos para los moduladores endógenos y exógenos de CaSR.
- Ofrece información sobre la modulación alostérica de los GPCR por pequeñas moléculas y ligandos naturales.
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