Cereblon (CRBN)–neosubstrate interface (CRBN–NS interface)

The Cereblon (CRBN)–neosubstrate interface is a dynamic structural site formed when a molecular glue degrader binds to the CRBN protein, which serves as the substrate receptor for the Cullin-RING ligase 4 (CRL4) E3 ubiquitin ligase complex [Fischer et al., 2014, Nature]. In its native state, CRBN targets specific endogenous substrates for ubiquitination; however, the binding of small-molecule immunomodulatory imide drugs (IMiDs) like thalidomide analogs alters the surface topology of CRBN, creating a 'neo-morphe' surface [Petzold et al., 2016, Nature]. This altered interface enables the recruitment of 'neosubstrates'—proteins such as IKZF1, IKZF3, or GSPT1—that lack natural affinity for CRBN, leading to their polyubiquitination and subsequent degradation by the 26S proteasome [Ito et al., 2010, Science]. This interface is the primary pharmacological target for treating hematologic malignancies like multiple myeloma, where the degradation of transcription factors Ikaros and Aiolos triggers apoptosis in malignant B-cells [Kronke et al., 2014, Science]. Beyond oncology, the CRBN–neosubstrate interface is a focal point for the development of novel molecular glues and Proteolysis Targeting Chimeras (PROTACs) aimed at degrading previously 'undruggable' targets [Chamberlain et al., 2019, Nat Chem Biol]. Precise characterization of this interface is essential for improving drug selectivity and avoiding off-target degradation of proteins like SALL4, which is associated with clinical teratogenicity [Matyskiela et al., 2018, Nature].

Other names

CRBN-IMiD-neosubstrate complexCereblon-glue-substrate interfaceCRL4-CRBN neosubstrate recruitment siteCRBN-MGD interface

Molecular glue degradation: the drug binds to the thalidomide-binding domain (TBD) of CRBN, reshaping the protein surface to facilitate the recruitment of a specific neosubstrate via a structural degron, resulting in neosubstrate ubiquitination and proteasomal degradation [Sievers et al., 2018, Science].