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Un inhibidor competitivo atrapa a LeuT en una conformación abierta hacia afuera
Satinder K Singh1, Chayne L Piscitelli, Atsuko Yamashita
1Vollum Institute, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA.
Science (New York, N.Y.)
|December 17, 2008
Resumen
Los transportadores secundarios mueven las moléculas a través de las membranas. Los estudios sobre el transportador de leucina (LeuT) revelan cómo los sustratos causan cambios conformacionales y cómo los inhibidores como el triptófano (Trp) bloquean el transporte al atrapar al transportador en un estado abierto.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
- Transporte de la membrana Transporte de la membrana
Sus antecedentes:
- Los transportadores secundarios son proteínas de membrana cruciales que facilitan el transporte de moléculas e iones a través de las dos capas celulares.
- Comprender los cambios conformacionales dinámicos, los mecanismos de transporte y la inhibición competitiva de estos transportadores es esencial, pero sigue siendo un desafío.
Objetivo del estudio:
- Para dilucidar los cambios conformacionales durante el transporte del sustrato en transportadores secundarios.
- Para investigar el mecanismo de la inhibición competitiva utilizando el transportador de leucina (LeuT) como un sistema modelo.
Principales métodos:
- Se emplearon estudios cristalográficos para determinar las estructuras de LeuT en complejo con sustratos e inhibidores.
- Se realizaron ensayos funcionales para evaluar la actividad de transporte y los estados conformacionales de LeuT.
Principales resultados:
- Se encontró que varios sustratos de aminoácidos inducían un estado de conformación ocluida similar en LeuT.
- Se observó que el inhibidor competitivo triptófano (Trp) atrapaba a LeuT en una conformación abierta hacia afuera.
- Se identificó un sitio de unión secundario que involucra residuos de la puerta extracelular (Arg30 y Asp404), que media la permeación inhibidor / sustrato.
Conclusiones:
- El estudio revela distintos estados conformacionales inducidos por sustratos e inhibidores en LeuT.
- El sitio de unión secundaria identificado pone de relieve el doble papel de los residuos de compuertas en la permeación del sustrato y la regulación del transportador.
- Estos hallazgos proporcionan información sobre el mecanismo de transporte y la inhibición competitiva de los simportadores de sodio del neurotransmisor.
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