Cullin-RING ligase 4-Cereblon E3 ubiquitin ligase complex (CRL4-CRBN)

The Cullin-RING ligase 4-Cereblon (CRL4-CRBN) E3 ubiquitin ligase complex is a multi-protein machinery essential for cellular protein homeostasis through the ubiquitin-proteasome system (PMID: 20223979). The complex is composed of the scaffold protein Cullin 4 (CUL4A or CUL4B), the RING-finger protein RBX1, the adaptor protein DDB1, and the substrate receptor Cereblon (CRBN), which provides the specificity for target proteins (PMID: 24284194). It is the primary therapeutic target for immunomodulatory imide drugs (IMiDs), such as thalidomide and its derivatives, which function as molecular glues (PMID: 24284195). These drugs bind to a hydrophobic pocket in CRBN, enabling the recruitment and subsequent degradation of neo-substrates like Ikaros (IKZF1) and Aiolos (IKZF3), which are vital for the survival of B-cell malignancies (PMID: 25979828). Beyond its role in cancer therapy, the complex is involved in limb development and its modulation is responsible for the well-known teratogenic effects of thalidomide (PMID: 20223979). Understanding the structural biology of the CRL4-CRBN complex has paved the way for the development of proteolysis-targeting chimeras (PROTACs) and next-generation degraders (PMID: 27281222). This complex represents a cornerstone of targeted protein degradation strategies in modern drug discovery.

Other names

CRL4-CRBN complexCUL4-DDB1-CRBN complexCereblon E3 ligase complexCRL4(CRBN)

Drugs act as molecular glues that bind to the Cereblon (CRBN) subunit, altering the substrate binding surface to recruit and ubiquitinate neo-substrates (e.g., IKZF1, IKZF3, CSNK1A1, GSPT1) for proteasomal degradation (PMID: 24284194, PMID: 24284195).