Cereblon–DNA damage-binding protein 1 E3 ubiquitin ligase complex (CRL4-CRBN) (CRL4-CRBN)

The Cereblon–DNA damage-binding protein 1 (CRBN–DDB1) E3 ubiquitin ligase complex, often referred to as CRL4-CRBN, is a multi-protein machinery that tags specific proteins with ubiquitin for degradation by the 26S proteasome (Ito et al., 2010, Science). The complex is composed of the substrate receptor Cereblon (CRBN), the adapter protein DDB1, the scaffold protein Cullin-4A (CUL4A) or Cullin-4B (CUL4B), and the RING-finger protein RBX1 (also known as ROC1) (Fischer et al., 2014, Nature). It is the primary molecular target for immunomodulatory imide drugs (IMiDs) like thalidomide, lenalidomide, and pomalidomide, which bind to the CRBN subunit and alter its substrate specificity (Chamberlain et al., 2014, Nature Structural & Molecular Biology). This "molecular glue" mechanism leads to the degradation of neo-substrates such as the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), which are essential for the survival of multiple myeloma cells (Kronke et al., 2014, Science). Beyond its role in cancer, the complex is involved in limb development and DNA damage repair, and its dysfunction is linked to autosomal recessive intellectual disability (Higgins et al., 2004, American Journal of Human Genetics). Additionally, the CRBN–DDB1 complex is widely utilized in the development of Proteolysis Targeting Chimeras (PROTACs) to induce the targeted degradation of various disease-causing proteins (Bondeson et al., 2015, Nature Chemical Biology). This versatility makes it a cornerstone of modern proximity-based pharmacology and targeted protein degradation strategies.

Other names

CRBN-DDB1-CUL4A-RBX1 complexCullin-RING ligase 4-CereblonCRL4CRBNCereblon E3 ligase complex

Molecular glue degradation of neo-substrates (e.g., IKZF1, IKZF3, CK1α) and recruitment of E3 ligase for Proteolysis Targeting Chimeras (PROTACs)