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Bases estructurales del mecanismo de acceso alternado en un transportador de ácido biliar
Xiaoming Zhou1, Elena J Levin2, Yaping Pan3
11] Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2] Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA [3].
Nature
|December 10, 2013
Resumen
Los transportadores de ácido biliar como el ASBT son cruciales para el metabolismo del colesterol y son objetivos potenciales de medicamentos. Las nuevas estructuras revelan cómo estos transportadores mueven los ácidos biliares y el sodio a través de las membranas, ayudando al desarrollo de fármacos.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
- Transporte de la membrana Transporte de la membrana
Sus antecedentes:
- Los ácidos biliares, sintetizados a partir del colesterol, son esenciales para la absorción de lípidos y se someten a la recirculación enterohepática.
- Los transportadores de ácido biliar dependientes de Na, NTCP y ASBT, facilitan la reabsorción de ácido biliar en humanos.
- ASBT es un objetivo farmacológico clave para la hipercolesterolemia debido a su papel en la reabsorción de ácido biliar.
Objetivo del estudio:
- Para dilucidar los mecanismos moleculares del transporte de ácido biliar y sodio por ASBT.
- Comprender las bases estructurales de la selectividad del sustrato y la dinámica del transporte.
- Proporcionar ideas para el diseño racional de fármacos dirigidos a ASBT.
Principales métodos:
- Se determinaron dos estructuras cristalinas del homólogo de Yersinia frederiksenii ASBT (ASBTYf) en un entorno de lípidos.
- Se analizaron los cambios estructurales asociados con el transporte acoplado de Na(+) y ácidos biliares.
- Estructuras comparadas para inferir mecanismos y vías de transporte.
Principales resultados:
- Reveló una gran rotación de cuerpo rígido del dominio de unión al sustrato en ASBTYf.
- Acceso alternado demostrado de la región "cruzada" conservada desde ambos lados de la membrana.
- Proporcionó la base estructural para la translocación de ácido biliar y Na ((+) a través de la membrana.
Conclusiones:
- El mecanismo de rotación de dominio observado explica cómo ASBT facilita el transporte acoplado.
- Las percepciones estructurales informan la comprensión del movimiento de ácido biliar y Na (((+).
- Estos hallazgos avanzan en el desarrollo de terapias basadas en ASBT para trastornos relacionados con el colesterol.
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