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El EmrE antiparalelo exporta drogas mediante el intercambio entre estructuras asimétricas

Emma A Morrison¹, Gregory T DeKoster, Supratik Dutta

¹Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

|December 20, 2011

Resumen

Se estudiaron los transportadores de Escherichia coli EmrE, cruciales para la resistencia a los medicamentos. Encontramos monómeros EmrE antiparalelos asimétricos que intercambian dinámicamente entre estados orientados hacia adentro y hacia afuera, lo que explica la simetría funcional.

Área de la Ciencia:

La bioquímica es la bioquímica.
Biología Estructural Biología estructural.
Transporte de la membrana Transporte de la membrana

Sus antecedentes:

Los pequeños transportadores de resistencia a múltiples fármacos (SMR, por sus siglas en inglés) son clave para comprender los mecanismos de transporte activo.
EmrE de Escherichia coli exporta sustratos catiónicos poliaromáticos, lo que confiere resistencia a múltiples fármacos.
La topología homodimérica de EmrE ha sido objeto de un importante debate científico.

Objetivo del estudio:

Para aclarar la dinámica conformacional y la topología de la membrana del transportador EmrE.
Para conciliar la asimetría estructural de EmrE con la simetría funcional observada en su sitio activo.

Principales métodos:

Solución Experimentos de dinámica de resonancia magnética nuclear (RMN) en bicélulas.
La transferencia de energía de resonancia Förster (FRET) para determinar la orientación del monómero.
Mejora de la relajación paramagnética (PRE) RMN para evaluar la accesibilidad al agua.

Principales resultados:

Demostró que los monómeros EmrE antiparalelos asimétricos intercambian entre conformaciones orientadas hacia adentro y hacia afuera.
Se midieron cuantitativamente las dinámicas globales de intercambio conformacional de EmrE. ligado al sustrato.
Se reveló la accesibilidad diferencial al agua de los monómeros dentro del dímero EmrE, lo que indica una asimetría.

Conclusiones:

EmrE exhibe "simetría dinámica", donde los monómeros asimétricos logran simetría funcional a través del intercambio conformacional.
Este mecanismo dinámico explica cómo EmrE mantiene la actividad de transporte a pesar de la asimetría estructural.
Proporciona una nueva perspectiva sobre los requisitos mínimos para el transporte activo en proteínas de membrana.

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