CRL4–cereblon E3 ubiquitin ligase complex (CRL4(CRBN))

The CRL4–cereblon E3 ubiquitin ligase complex is a multiprotein E3 ubiquitin ligase composed primarily of Cullin-4 (CUL4), DDB1, RBX1, and the substrate receptor cereblon (CRBN). This complex targets specific substrate proteins for ubiquitination, marking them for proteasomal degradation. Cereblon directs substrate specificity and is the direct binder and modulator for immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide, which reprogram CRBN to target different substrates—most notably the transcription factors IKZF1 and IKZF3—resulting in anti-cancer and immunomodulatory activity as well as significant teratogenic potential[4][5][6][7]. The complex’s function is implicated in both physiological protein homeostasis and disease processes through its broad and drug-reprogrammable substrate selectivity.

Other names

CRBN E3 ubiquitin ligase complexDDB1–CRBN E3 ubiquitin ligase complexCUL4–RBX1–DDB1–CRBN complexCRL4CRBN complexDCX E3 ligase complex (DDB1-CUL4-X-box)

Molecular glue degradation: immunomodulatory drugs (IMiDs) bind CRBN, reprogramming substrate specificity, driving ubiquitination and proteasomal degradation of transcription factors (e.g., IKZF1, IKZF3) and other neo-substrates[4][5][6]. - Inhibition/blocking of endogenous substrate binding (e.g., MEIS2)[5][6].