biostudies-literatureIchikawa SNIGMS NIH HHS775-782https://www.ebi.ac.uk/biostudies/studies/S-EPMC10316063biostudies-literatureUnknown610(7933)The ubiquitin E3 ligase substrate adapter cereblon (CRBN) is a target of thalidomide and lenalidomide¹, therapeutic agents used in the treatment of haematopoietic malignancies^2-4 and as ligands for targeted protein degradation^5-7. These agents are proposed to mimic a naturally occurring degron; however, the structural motif recognized by the thalidomide-binding domain of CRBN remains unknown. Here we report that C-terminal cyclic imides, post-translational modifications that arise from intramolecular cyclization of glutamine or asparagine residues, are physiological degrons on substrates for CRBN. Dipeptides bearing the C-terminal cyclic imide degron substitute for thalidomide when embedded within bifunctional chemical degraders. Addition of the degron to tNatureThe E3 ligase adapter cereblon targets the C-terminal cyclic imide degron.PMC10316063R01 GM114537Vallavoju NPratt MRWang BFlaxman HAWoo CMShen DLloyd HCIchikawa SXu WfalseThe E3 ligase adapter cereblon targets the C-terminal cyclic imide degron.The ubiquitin E3 ligase substrate adapter cereblon (CRBN) is a target of thalidomide and lenalidomide¹, therapeutic agents used in the treatment of haematopoietic malignancies^2-4 and as ligands for targeted protein degradation^5-7. These agents are proposed to mimic a naturally occurring degron; however, the structural motif recognized by the thalidomide-binding domain of CRBN remains unknown. Here we report that C-terminal cyclic imides, post-translational modifications that arise from intramolecular cyclization of glutamine or asparagine residues, are physiological degrons on substrates for CRBN. Dipeptides bearing the C-terminal cyclic imide degron substitute for thalidomide when embedded within bifunctional chemical degraders. Addition of the degron to t2022-01-01T00:00:00Z2022 Oct2026-05-29T09:06:00.356Z2025-02-19T03:21:01.154ZS-EPMC103160633626152910.1038/s41586-022-05333-5