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Preparation and Delivery of Protein Microcrystals in Lipidic Cubic Phase for Serial Femtosecond Crystallography
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La estructura cristalina de la proteína de activación de la 5-lipoxigenasa humana unida al inhibidor
Andrew D Ferguson1, Brian M McKeever, Shihua Xu
1Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
Science (New York, N.Y.)
|June 30, 2007
Resumen
Los investigadores revelaron la base estructural para inhibir la biosíntesis de los leucotrienos. Comprender cómo se unen los inhibidores de FLAP ofrece una nueva vía para desarrollar tratamientos para enfermedades inflamatorias respiratorias y cardiovasculares.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
- Farmacología Farmacología.
Sus antecedentes:
- Los leucotrienos son mediadores inflamatorios clave derivados del ácido araquidónico.
- La biosíntesis de leucotrieno está implicada en enfermedades respiratorias y cardiovasculares.
- La proteína de membrana integral FLAP (proteína activadora de la 5-lipoxigenasa) es crucial para la producción de leucotrienos.
Objetivo del estudio:
- Para dilucidar el mecanismo estructural de la inhibición de la biosíntesis de leucotrienos.
- Proporcionar una base estructural para el diseño de nuevos inhibidores de FLAP.
Principales métodos:
- Se empleó cristalografía de rayos X para determinar las estructuras.
- La FLAP humana fue cristalizada en complejo con dos inhibidores de la biosíntesis de leucotrienos distintos.
- Se obtuvieron estructuras de alta resolución (4.0 y 4.2 angstroms).
Principales resultados:
- Las estructuras cristalinas revelan que los inhibidores se unen dentro de las bolsas de FLAP incrustadas en la membrana.
- Este modo de unión explica cómo los inhibidores impiden el acceso del sustrato (ácido araquidónico) al FLAP.
- Las estructuras ilustran el mecanismo por el cual se impide que el FLAP transfiera el ácido araquidónico a la 5-lipoxigenasa.
Conclusiones:
- Las estructuras determinadas proporcionan información crítica sobre la función de FLAP en la biosíntesis de leucotrieno.
- Esta información estructural sirve como base para el diseño racional de fármacos.
- Se podrían desarrollar estrategias terapéuticas dirigidas a la FLAP para tratar afecciones inflamatorias respiratorias y cardiovasculares.
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