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Estructura cristalina del receptor σ1 humano

Hayden R Schmidt¹, Sanduo Zheng¹, Esin Gurpinar¹

¹Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.

|April 5, 2016

Resumen

El receptor σ1 humano, implicado en trastornos neurológicos, tiene una estructura trímera recientemente revelada. Esta proteína del retículo endoplasmático se une a diversos medicamentos a través de un dominio plástico parecido a la cupina, lo que aclara su función.

Área de la Ciencia:

La neurociencia
Biología estructural
Farmacología

Sus antecedentes:

El receptor σ1 humano es una proteína transmembrana residente en el retículo endoplasmático relacionada con la depresión, la adicción a las drogas, el dolor neuropático y la esclerosis lateral amiotrófica.
Es un aislado evolutivo sin similitudes conocidas de la familia de proteínas, y su arquitectura molecular y regulación de fármacos se entienden mal.

Objetivo del estudio:

Para aclarar la arquitectura molecular y el mecanismo de unión de ligando del receptor σ1 humano.
Comprender cómo los compuestos químicamente diversos interactúan con el receptor σ1.

Principales métodos:

Se utilizó la cristalografía de rayos X para determinar la estructura del receptor σ1 humano.
Se obtuvieron estructuras complejas con dos ligandos distintos: PD144418 y 4-IBP.

Principales resultados:

El receptor σ1 humano adopta una arquitectura trímera, con cada protómero que contiene un solo dominio transmembrana.
Un dominio de barril β tipo cupina forma el sitio de unión del ligando, ubicado centralmente y con una gran cavidad hidrofóbica.
El receptor exhibe una plasticidad significativa en la unión de ligandos, acomodando ligandos químicamente diferentes en posiciones similares.

Conclusiones:

El estudio revela la arquitectura general, el estado de oligomerización y el mecanismo de unión de ligando del receptor σ1 humano.
Los hallazgos proporcionan una base estructural para comprender la interacción del receptor σ1 con compuestos similares a los medicamentos y su papel en la enfermedad.

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