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Estructura y mecanismo del transportador de fructosa GLUT5 en mamíferos
Norimichi Nomura1,2,3, Grégory Verdon4,5,6, Hae Joo Kang4,5,6
1Department of Cell Biology, Graduate School of Medicine, Kyoto University, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.
Nature
|September 30, 2015
Resumen
La actividad alterada del transportador de fructosa GLUT5 está relacionada con la diabetes y la obesidad. El análisis estructural revela un mecanismo de poros cerrados y una sola mutación que cambia GLUT5
Área de la Ciencia:
- La bioquímica
- Biología estructural
- Biología molecular
Sus antecedentes:
- La actividad alterada del transportador de fructosa GLUT5 está implicada en la diabetes tipo 2, la obesidad y ciertos cánceres.
- GLUT5 es un transportador monosacárido clave con potencial como objetivo de fármaco.
Objetivo del estudio:
- Para aclarar la base estructural de la función GLUT5 y el transporte del sustrato.
- Investigar el mecanismo de transporte de monosacáridos en GLUT5.
Principales métodos:
- Determinación de las estructuras cristalinas de Rattus norvegicus GLUT5 (con orientación hacia el exterior) y Bos taurus GLUT5 (con orientación hacia el interior).
- Comparó las estructuras de GLUT5 con las de GLUT1 y E. coli XylE humanos para comprender los mecanismos de transporte.
- Se utilizaron comparaciones estructurales para identificar los residuos clave para la especificidad del sustrato.
Principales resultados:
- Estructuras GLUT5 resueltas en distintas conformaciones abiertas, revelando un pliegue de la superfamilia facilitadora principal.
- Se demostró que una mutación de un solo punto puede alterar la preferencia del sustrato de GLUT5 de la fructosa a la glucosa.
- Se propuso un mecanismo de transporte de "poros abiertos" que implicaba reorganizaciones de hélices en paquetes transmembrana TM7 y TM10.
Conclusiones:
- Los conocimientos estructurales sobre GLUT5 proporcionan una base para comprender su papel en los trastornos metabólicos.
- El mecanismo de "poros cerrados" identificado ofrece una nueva perspectiva sobre la función del transportador de monosacáridos.
- Los hallazgos allanan el camino para el diseño de inhibidores dirigidos para las enfermedades relacionadas con GLUT5.
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