9DQD
cryo-EM structure of human Cereblon/DDB1 in complex with a non-traditional CRBN binder
This is a non-PDB format compatible entry.
Summary for 9DQD
| Entry DOI | 10.2210/pdb9dqd/pdb |
| EMDB information | 47111 |
| Descriptor | Protein cereblon, DNA damage-binding protein 1, 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 | 147335.88 |
| Authors | Zhu, J.,Pagarigan, B. (deposition date: 2024-09-23, release date: 2024-12-25, Last modification date: 2025-01-29) |
| Primary citation | Lejava, A.,Miseo, G.A.,Phan, T.,Zhu, J.,Powers, H.L.,Li, J.,Mortensen, D.S.,Zapf, C.W.,Khambatta, G.,Buenviaje, J.,Holmberg-Douglas, N. Development of a Buchwald-Hartwig Amination for an Accelerated Library Synthesis of Cereblon Binders. Acs Med.Chem.Lett., 16:89-95, 2025 Cited by PubMed Abstract: In recent years, targeted protein degradation (TPD) has emerged as a powerful therapeutic modality utilizing both heterobifunctional ligand-directed degraders (LDDs) and molecular glues (e.g., CELMoDs) to recruit E3 ligases for inducing polyubiquitination and subsequent proteasomal degradation of target proteins. The immunomodulatory drugs lenalidomide and pomalidomide bind to cereblon (CRBN), a substrate receptor of the CRL4A E3 ligase complex, to initiate degradation of neosubstrates critical for cell survival. Recently, nonlenalidomide or pomalidomide CRBN binders, known as alternate glutarimides, have gained popularity, offering potential degraders with varying physicochemical properties. Specifically, 3-substituted indazole derivatives have emerged as potent CRBN binders. We developed conditions for the direct cross-coupling of unprotected glutarimides with amines, streamlining the synthesis of alternative CRBN binders. This manuscript describes the rapid synthesis of 30 CRBN binders, their characterization as potential degraders and a cryo-EM structure of the CRBN/DDB1 with a representative compound (). PubMed: 39811117DOI: 10.1021/acsmedchemlett.4c00462 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3 Å) |
Structure validation
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