8D81

Cereblon~DDB1 bound to Pomalidomide

Summary for 8D81

• Entry DOI: 10.2210/pdb8d81/pdb
• EMDB information: 27234 27235 27236 27237 27238 27239 27240 27241 27242
• Descriptor: DNA damage-binding protein 1, Protein cereblon, ZINC ION, ... (4 entities in total)
• Functional Keywords: crl4, ubiquitin, e3, cereblon, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 144289.41

Authors

Watson, E.R.,Lander, G.C. (deposition date: 2022-06-07, release date: 2022-07-20, Last modification date: 2024-06-12)

Primary citation

Watson, E.R.,Novick, S.,Matyskiela, M.E.,Chamberlain, P.P.,H de la Pena, A.,Zhu, J.,Tran, E.,Griffin, P.R.,Wertz, I.E.,Lander, G.C.
Molecular glue CELMoD compounds are regulators of cereblon conformation.
Science, 378:549-553, 2022

PubMed 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.

PubMed: 36378961
DOI: 10.1126/science.add7574

Experimental method

ELECTRON MICROSCOPY (3.9 Å)