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

The **Cullin 4–RING E3 ubiquitin ligase–Cereblon complex** (CRL4–CRBN) is a multisubunit E3 ligase in which Cereblon (CRBN) acts as a substrate receptor in concert with cullin 4 (CUL4A/B), DNA damage-binding protein 1 (DDB1), and ring-box 1 (RBX1)[1][2][3]. CRL4–CRBN regulates proteasomal protein degradation by recognizing specific substrates for ubiquitination. Thalidomide and related drugs bind to the CRBN subunit, altering substrate specificity to promote degradation of transcription factors such as Ikaros (IKZF1) and Aiolos (IKZF3), which is critical for anti-tumor effects in multiple myeloma and related disorders[1][2][5]. The teratogenic effects of thalidomide are also mediated via CRL4–CRBN, underscoring clinical safety concerns[2][3]. The complex is now widely exploited for targeted protein degradation using "molecular glue" drugs and PROTACs[1][3]. CRBN's physiological functions extend to neurodevelopment and metabolic regulation, with growing evidence for additional roles and native substrates[3].

Other names

CRL4(CRBN)CRL4–cereblon complexCullin 4A–RING E3–CereblonDDB1–CUL4–RBX1–CRBN complexCRBN E3 ligase complexCereblon E3 ligase modulatory complex

"Molecular glue" that reprograms substrate specificity of CRL4–CRBN, leading to ubiquitination and proteasomal degradation of neosubstrates (e.g., Ikaros, Aiolos, CK1α, GSPT1) upon drug binding[1][2][5]. PROTAC-mediated ternary complex formation resulting in target protein degradation[3].