Molecular glue CELMoD compounds are regulators of cereblon conformation

• DOI: 10.1126/science.add7574
• Publication Date: 2022-11-03T17:58:37Z
• Authors: Edmond R. Watson; Scott Novick; Mary E. Matyskiela; Philip P. Chamber...; Andres H. de la Peña; Jinyi Zhu; Eileen Tran; Patrick R. Griffin; Ingrid E. Wertz; Gabriel C. Lander
• Keywords: Cereblon; Ubiquitin-Protein Ligases

Cereblon (CRBN) is a ubiquitin ligase (E3) substrate receptor protein co-opted by CRBN E3 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 allostery of drug-induced neosubstrate binding remains unclear. We performed cryo-electron microscopy analyses DNA damage-binding 1 (DDB1)-CRBN apo complex and compared these structures with DDB1-CRBN in presence CELMoD compounds alone complexed neosubstrates. Association to TBD necessary sufficient triggering allosteric rearrangement from an open conformation canonical closed conformation. The Ikaros only stably associates conformation, illustrating importance compound efficacy informing structure-guided design strategies improve therapeutic efficacy.