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Estructura y dinámica del receptor activo de la hormona paratiroidea humana-1

Li-Hua Zhao¹, Shanshan Ma^1,2, Ieva Sutkeviciute³

¹The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Science (New York, N.Y.)

|April 13, 2019

Resumen

Determinamos la estructura cryo-EM del receptor de la hormona paratiroidea-1 (PTH1R) unido a un análogo de PTH y a la proteína G. Esto revela cómo la activación de PTH1R implica el retorcimiento de la hélice transmembrana 6 y las conformaciones dinámicas del dominio extracelular.

Área de la Ciencia:

La bioquímica
Biología estructural
Farmacología

Sus antecedentes:

El receptor de la hormona paratiroidea 1 (PTH1R) es un receptor acoplado a proteínas de clase B G crucial para la homeostasis del calcio.
El PTH1R es un objetivo terapéutico clave para enfermedades como la osteoporosis y el hipoparatiroidismo.

Objetivo del estudio:

Aclarar los mecanismos estructurales subyacentes a la activación de PTH1R por un análogo de PTH de acción prolongada.
Para visualizar la interacción entre PTH1R, un ligando unido y una proteína G estimulante.

Principales métodos:

Para determinar la estructura de alta resolución se empleó la criomicroscopia electrónica.
Se resolvió la estructura del complejo PTH1R humano con un análogo de PTH y una proteína G.

Principales resultados:

El N-terminal del análogo PTH se inserta en el dominio transmembrana del receptor (TMD), causando un desenrollo parcial y una torcedura en la hélice transmembrana 6.
Esta reorganización estructural facilita el acoplamiento de la proteína G.
El dominio extracelular del receptor exhibe múltiples conformaciones, lo que indica estados estructurales dinámicos.

Conclusiones:

El estudio proporciona información a nivel atómico sobre la base estructural de la activación de PTH1R.
Comprender estas dinámicas es vital para diseñar nuevas terapias dirigidas a la PTH1R para enfermedades óseas y trastornos metabólicos.

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