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Expression, Detergent Solubilization, and Purification of a Membrane Transporter, the MexB Multidrug Resistance Protein
Published on: December 3, 2010
Bases estructurales para el mecanismo de extrusión de fármacos mediante un transportador multidrogas MATE
Yoshiki Tanaka1, Christopher J Hipolito, Andrés D Maturana
1RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Nature
|March 29, 2013
Resumen
Los investigadores aclararon las estructuras de un transportador clave de extrusión de compuestos tóxicos y multidrogas (MATE), revelando mecanismos de extrusión de fármacos e identificando potentes inhibidores de péptidos para aplicaciones terapéuticas.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
- Biología Molecular Biología Molecular
Sus antecedentes:
- Los transportadores de extrusión de compuestos tóxicos y multidrogas (MATE) son proteínas de membrana cruciales involucradas en el eflujo xenobiótico.
- Estos transportadores contribuyen a la resistencia a múltiples fármacos en los patógenos bacterianos y las células cancerosas, limitando la eficacia de los fármacos.
- El desarrollo de inhibidores del transportador MATE es esencial para mejorar los resultados terapéuticos.
Objetivo del estudio:
- Para determinar las estructuras cristalinas de alta resolución del transportador MATE impulsado por H(+) de Pyrococcus furiosus.
- Para dilucidar los mecanismos estructurales subyacentes a la extrusión del sustrato y la inhibición por pequeñas moléculas y péptidos.
- Para identificar compuestos de plomo potenciales para el desarrollo de nuevos inhibidores de MATE.
Principales métodos:
- Se empleó cristalografía de rayos X para obtener estructuras del transportador MATE en estados de forma apo y complejos.
- Se realizaron análisis funcionales para evaluar el impacto de las características estructurales en la actividad del transportista.
- Se utilizó la selección in vitro para identificar péptidos tioéter-macrocíclicos con potencial inhibidor.
Principales resultados:
- Se resolvieron dos conformaciones distintas de la forma apo del transportador MATE de P. furiosus.
- Las estructuras revelaron cómo la protonación de Asp 41 desencadena cambios conformacionales que conducen a la extrusión del sustrato.
- Se demostró que los péptidos macrocíclicos se unen a la hendidura central, con modos de unión distintos que se correlacionan con la potencia inhibidora.
Conclusiones:
- El estudio proporciona información estructural detallada sobre el mecanismo del eflujo de drogas mediado por el transportador MATE.
- Se identificó un potente inhibidor del péptido tioéter-macrocíclico dirigido a la cavidad del lóbulo N.
- Estos hallazgos sientan las bases para el diseño de inhibidores efectivos contra los transportadores MATE para aplicaciones clínicas.
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