8d7z

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

spinqualitylabelsall models 8d7z, resolution 3.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8d7z is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.1Å Ligands: QFC, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. 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 Science. 2022 Nov 4;378(6619):549-553. doi: 10.1126/science.add7574. Epub 2022 , Nov 3. PMID:36378961 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also DNA damage-binding protein

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