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Bases estructurales para el reconocimiento de ligandos alostéricos en el receptor de quimiocinas CC humano 7

Kathrin Jaeger¹, Steffen Bruenle¹, Tobias Weinert¹

¹Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institute, Villigen PSI.

|August 24, 2019

Resumen

Los investigadores determinaron la estructura cristalina del receptor de quimiocinas CC 7 (CCR7) unido a un ligando, revelando un sitio de unión alostérico. Este descubrimiento ayuda en el desarrollo de nuevas terapias contra el cáncer dirigidas a las metástasis mediadas por CCR7.

Área de la Ciencia:

Biología estructural
Inmunología
Farmacología

Sus antecedentes:

El receptor de quimiocinas CC 7 (CCR7) regula el tráfico de células inmunes, crucial tanto para la homeostasis como para la metástasis del cáncer.
El papel de CCR7 en la metástasis de los ganglios linfáticos lo convierte en un objetivo terapéutico significativo en oncología.

Objetivo del estudio:

Para aclarar la base estructural de la unión del ligando CCR7.
Identificar y caracterizar los nuevos moduladores alostéricos de CCR7 para el tratamiento del cáncer.

Principales métodos:

Cristalografía de rayos X de CCR7 humano fusionado con Sialidasa NanA a una resolución de 2,1 Å.
En el cribado de silicio de un repositorio de compuestos.
Control automatizado de la estabilidad térmica para la identificación de compuestos.

Principales resultados:

La estructura cristalina reveló un ligando (Cmp2105) unido a un bolsillo alostérico intracelular cerca del sitio de unión a la proteína Gi.
Se observó una fracción de sulfonamida interactuando con los residuos conservados entre la hélice transmembrana 7 y la hélice 8.
Se identificaron nuevos moduladores de CCR7 (CS-1, CS-2) y un conocido antagonista de CXCR1-CXCR2 (Navarixin).

Conclusiones:

Los conocimientos estructurales facilitan el diseño racional de los antagonistas alostéricos del CCR7.
Los moduladores identificados ofrecen potencial para estrategias de terapia de cáncer de múltiples objetivos.
Este enfoque permite el descubrimiento y la modulación eficientes de los antagonistas de los receptores de quimiocinas.

Palabras clave:

CCR7 (en inglés)Receptores acoplados a proteínas G Modulación alostérica el cáncer Receptores de las quimiocinas estructura de cristal Metástasis en los ganglios linfáticos Proteínas de membrana análisis de drogas basado en la estructura

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