LAUSR

Cereblon (CRBN) is a ubiquitin ligase (E3) substrate receptor protein co-opted by CRBN E3 ligase modulatory drug (CELMoD) agents that target therapeutically relevant proteins for degradation. Prior crystallographic studies defined the drug-binding site within CRBN’s thalidomide-binding domain (TBD), but the allostery of drug-induced neosubstrate binding remains unclear. We performed cryo–electron microscopy analyses of the DNA damage-binding protein 1 (DDB1)–CRBN apo complex and compared these structures with DDB1-CRBN in the presence of CELMoD compounds alone and complexed with neosubstrates. Association of CELMoD compounds to the TBD is necessary and sufficient for triggering CRBN allosteric rearrangement from an open conformation to the canonical closed conformation. The neosubstrate Ikaros only stably associates with the closed CRBN conformation, illustrating the importance of allostery for CELMoD compound efficacy and informing structure-guided design strategies to improve therapeutic efficacy. Description Closed complex for protein degradation The ability to target endogenous proteins for degradation with small molecules has opened up avenues for treating a wide range of diseases. Watson et al. investigated how a class of these molecules called CELMoDs (CRBN E3 ligase modulatory drugs) alter the conformational landscape of cereblon (CRBN), the enzyme that recognizes and marks substrates for degradation. The authors found that CELMoD compounds trigger a conformational rearrangement of CRBN from an entirely open and defunct form to an active closed form, but only for a subset of CRBN proteins. Next-generation CELMoDs, which are more effective therapies, appear to activate many more CRBN proteins by promoting closure much more efficiently, and future drug development may be able to harness this allosteric effect to improve efficacy. —MAF Cereblon modulatory drugs influence the conformational landscape of cereblon to induce neosubstrate binding and degradation.