Cereblon E3 ubiquitin ligase complex (CRL4-CRBN) (CRBN)

Cereblon (CRBN) functions as the substrate recognition component of the CRL4-CRBN E3 ubiquitin ligase complex, which also comprises Cullin-4A (CUL4A), DNA damage-binding protein 1 (DDB1), and Regulator of Cullins 1 (ROC1) [UniProt: Q96SW2]. This complex is responsible for the polyubiquitination of specific protein substrates, marking them for subsequent degradation by the 26S proteasome [PubMed: 20223979]. CRBN is the primary molecular target for immunomodulatory imide drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide, which bind to a hydrophobic pocket on its surface [PubMed: 24284321]. This binding event creates a neo-substrate interface, enabling the ligase to recruit and degrade non-native proteins, most notably the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), which are essential for the survival of certain hematologic malignancies [PubMed: 24284320]. Beyond its role with molecular glues, the CRBN-neo-substrate interface is extensively utilized in the development of Proteolysis-Targeting Chimeras (PROTACs) to achieve targeted degradation of diverse disease-causing proteins [PubMed: 25043012]. However, therapeutic modulation of CRBN is associated with significant safety risks, including severe teratogenicity and myelosuppression [PubMed: 26040720].

Other names

CereblonCRBNCRL4-CRBN complexCullin-RING ligase 4-CereblonCRL4(CRBN) E3 ubiquitin ligase

Molecular glue degradation and PROTAC-mediated targeted protein degradation via recruitment of neo-substrates to the E3 ligase complex.