EMD-27240
Cereblon-DDB1 bound to CC-92480 and Ikaros ZF1-2-3
EMD-27240
Single-particle3.1 Å
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Map released: 20/07/2022
Last modified: 12/06/2024
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
Sample: Cereblon-DDB1 bound to CC-92480 and Ikaros
Fitted models: 8d7z (Avg. Q-score: 0.492)
Deposition Authors: Watson ER
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Molecular glue CELMoD compounds are regulators of cereblon conformation.
Watson ER
,
Novick S
,
Matyskiela ME,
Chamberlain PP,
H de la Pena A
,
Zhu J
,
Tran E,
Griffin PR
,
Wertz IE,
Lander GC
(2022) Science , 378 , 549 - 553
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(2022) Science , 378 , 549 - 553
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.
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.