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Estructura de la ligasa de ubiquitina DDB1-CRBN E3 en complejo con talidomida

Eric S Fischer¹, Kerstin Böhm¹, John R Lydeard²

¹1] Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland [2] University of Basel, Petersplatz 10, CH-4003 Basel, Switzerland.

|July 22, 2014

Resumen

Los fármacos inmunomoduladores (IMiDs), a pesar de su teratogenicidad en el pasado, ahora tratan los cánceres dirigiéndose a la ligasa de ubiquitina CRL4 (CRBN) E3. Nuevas estructuras revelan cómo las IMiDs se unen a CRBN, bloqueando algunos sustratos mientras promueven otros para la degradación de proteínas dirigidas.

Área de la Ciencia:

La bioquímica es la bioquímica.
Biología Molecular Biología Molecular
Descubrimiento de Drogas Descubrimiento de Drogas

Sus antecedentes:

La talidomida y sus derivados (lenalidomida, pomalidomida), conocidos como medicamentos inmunomoduladores (IMiD), son tratamientos efectivos para el mieloma múltiple y la displasia asociada a la deleción de 5q.
A pesar de su teratogenicidad, los IMiDs se dirigen a la E3 ubiquitin ligasa CUL4-RBX1-DDB1-CRBN (CRL4 ((CRBN)).
CRL4 ((CRBN) media la ubiquitinación y degradación de los factores de transcripción de la familia IKAROS IKZF1 y IKZF3.

Objetivo del estudio:

Para aclarar la base estructural de la unión de IMiD al complejo DDB1-CRBN.
Para identificar sustratos endógenos de CRL4 (CRBN).
Comprender el mecanismo por el cual los IMiD modulan la actividad de CRL.

Principales métodos:

Se utilizó la cristalografía de rayos X para determinar las estructuras del complejo DDB1-CRBN unido a la talidomida, la lenalidomida y la pomalidomida.
Se utilizó una pantalla imparcial para identificar sustratos endógenos de CRL4 (CRBN).

Principales resultados:

Las estructuras cristalinas revelan CRBN como el receptor de sustrato dentro de CRL4 (CRBN) que se une enantioselectivamente IMiDs.
El factor de transcripción homeobox MEIS2 fue identificado como un sustrato endógeno de CRL4 (CRBN).
Se demostró que los IMiD bloquean la unión de sustratos endógenos como MEIS2 a CRL4 (CRBN) durante el reclutamiento de IKZF1 o IKZF3 para la degradación.

Conclusiones:

CRBN actúa como un receptor de sustrato para CRL4 ((CRBN), mediando la unión IMiD y la ubiquitinación del sustrato.
Los IMiD exhiben una doble actividad: promueven la degradación de IKZF1/IKZF3 mientras inhiben la degradación de otros sustratos como MEIS2.
Este doble mecanismo pone de relieve el potencial de las pequeñas moléculas para modular con precisión la actividad de la E3 ubiquitina ligasa, ofreciendo nuevas estrategias terapéuticas.

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