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Updated: Jun 4, 2025

Genetically-encoded Molecular Probes to Study G Protein-coupled Receptors

Genetically-encoded Molecular Probes to Study G Protein-coupled Receptors

Published on: September 13, 2013

Bases moleculares de la detección de protones por los receptores acoplados a proteínas G

Matthew K Howard¹, Nicholas Hoppe², Xi-Ping Huang³

¹Tetrad graduate program, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Bioengineering and Therapeutic Science, University of California, San Francisco, San Francisco, CA 94143, USA.

|January 3, 2025

Resumen

Los receptores acoplados a proteínas G de detección de protones (GPCR) utilizan una red de residuos, no un solo sitio, para detectar cambios en el pH. Este descubrimiento avanza en la comprensión de cómo funcionan estos receptores cruciales.

Área de la Ciencia:

La bioquímica
Biología molecular
Biología estructural

Sus antecedentes:

Se sabe que tres receptores acoplados a proteínas G (GPCR) - GPR4, GPR65 y GPR68 - detectan el pH extracelular e influyen en varios procesos fisiológicos.
Los mecanismos precisos por los cuales los protones activan estos receptores siguen siendo en gran medida desconocidos.

Objetivo del estudio:

Para aclarar las bases estructurales y funcionales de la activación de protones en GPR4, GPR65 y GPR68.
Identificar los residuos y redes clave involucrados en el reconocimiento de protones y la transducción de señales.

Principales métodos:

Microscopía criolectrónica (crio-EM) para determinar las estructuras de los tres GPCR sensibles a los protones.
Escaneo mutativo profundo (DMS) para evaluar funcionalmente la importancia de los residuos individuales en la activación de la GPR68.
Simulaciones de dinámica molecular de pH constante para explorar la dinámica conformacional y los estados de protonación.

Principales resultados:

Las estructuras cryo-EM revelaron la disposición espacial de los residuos de detección de protones dentro de los receptores.
DMS identificó que ningún residuo es el único responsable del reconocimiento de protones en GPR68.
Se encontró que una red distribuida de residuos titulables, que abarca desde la superficie extracelular hasta el dominio transmembrana, era crítica para la activación.
Las simulaciones proporcionaron información sobre los patrones dinámicos de protonación y los estados conformacionales.

Conclusiones:

La detección de protones en estos GPCR está mediada por una compleja red de residuos titulables en lugar de un solo sitio de unión de protones.
Este estudio proporciona un marco integral para comprender el mecanismo de activación de los GPCR sensibles a los protones.
Los hallazgos ofrecen objetivos potenciales para intervenciones terapéuticas que modulan las vías de señalización sensibles al pH.

Palabras clave:

GPCR y sus derivados Crio-EM el protón detección de protones señalización La estructura

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