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La estructura cristalina del dominio A proviene de la subunidad alfa de la integrina CR3 (CD11b/CD18)

J O Lee¹, P Rieu, M A Arnaout

¹Laboratory of X-Ray Crystallography, Dana Farber Cancer Institute, Harvard Medical School Boston, Massachusetts 02115.

|February 24, 1995

Resumen

Los investigadores determinaron la estructura cristalina del dominio A de la cadena alfa CR3 de la integrina, revelando un nuevo sitio de unión del magnesio. Este hallazgo avanza en la comprensión de la adhesión celular y el desarrollo potencial de fármacos para afecciones relacionadas con la integrina.

Área de la Ciencia:

Biología estructural Biología estructural.
La bioquímica es la bioquímica.
Investigación de la adhesión celular.

Sus antecedentes:

Las integrinas son receptores cruciales de la superficie celular involucrados en las interacciones de la matriz célula-célula y célula-extracelular.
La cadena alfa de la integrina CR3 contiene un dominio A implicado en las funciones de adhesión.
Comprender la base estructural de las interacciones integrina-ligando es clave para desarrollar terapias.

Objetivo del estudio:

Para determinar la estructura cristalina de alta resolución del dominio A de la cadena alfa de la integrina CR3.3.
Para caracterizar el sitio de coordinación de iones metálicos dentro del dominio A.
Proponer un modelo general para los sitios de adhesión dependientes de iones metálicos (MIDAS) en las integrinas.

Principales métodos:

Cristalografía de rayos X de alta resolución.
Determinación y análisis de la estructura de las proteínas.
Caracterización bioquímica de la unión de los iones metálicos.

Principales resultados:

El dominio A de la cadena alfa CR3 de la integrina adopta el clásico pliegue alfa/beta de Rossmann.
Se identificó un inusual sitio de coordinación Mg2+ en la superficie del dominio A.
Se descubrió que una cadena lateral de glutamato de una molécula adyacente del dominio A era un ligando coordinador.
Se propone que este sitio sea un sitio de adhesión dependiente de iones metálicos generales (MIDAS) para la unión de ligandos de proteínas.
Se propone que exista un motivo MIDAS dentro de un dominio A modificado de las subunidades beta de la integrina.

Conclusiones:

La estructura cristalina determinada proporciona una base para el modelado de otros miembros de la superfamilia de dominio A.
La identificación del sitio MIDAS ofrece información sobre el mecanismo de adhesión mediada por integrina.
Esta información estructural puede guiar el desarrollo de nuevos fármacos dirigidos a las vías de adhesión.

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