EMD-27240

Single-particle
3.1 Å
EMD-27240 Deposition: 07/06/2022
Map released: 20/07/2022
Last modified: 12/06/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-27240

Cereblon-DDB1 bound to CC-92480 and Ikaros ZF1-2-3

EMD-27240

Single-particle
3.1 Å
EMD-27240 Deposition: 07/06/2022
Map released: 20/07/2022
Last modified: 12/06/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: Cereblon-DDB1 bound to CC-92480 and Ikaros
Fitted models: 8d7z (Avg. Q-score: 0.492)

Deposition Authors: Watson ER , Lander GC
Molecular glue CELMoD compounds are regulators of cereblon conformation.
PUBMED: 36378961
DOI: doi:10.1126/science.add7574
ISSN: 1095-9203
ASTM: SCIEAS
Abstract:
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.