6BN7
Crystal structure of DDB1-CRBN-BRD4(BD1) complex bound to dBET23 PROTAC.
Summary for 6BN7
| Entry DOI | 10.2210/pdb6bn7/pdb |
| Descriptor | DNA damage-binding protein 1, Protein cereblon, Bromodomain-containing protein 4, ... (5 entities in total) |
| Functional Keywords | protac, degrader, e3 ligase, crbn, ligase |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 165480.97 |
| Authors | Nowak, R.P.,DeAngelo, S.L.,Buckley, D.,Bradner, J.E.,Fischer, E.S. (deposition date: 2017-11-16, release date: 2018-05-30, Last modification date: 2023-10-04) |
| Primary citation | Nowak, R.P.,DeAngelo, S.L.,Buckley, D.,He, Z.,Donovan, K.A.,An, J.,Safaee, N.,Jedrychowski, M.P.,Ponthier, C.M.,Ishoey, M.,Zhang, T.,Mancias, J.D.,Gray, N.S.,Bradner, J.E.,Fischer, E.S. Plasticity in binding confers selectivity in ligand-induced protein degradation. Nat. Chem. Biol., 14:706-714, 2018 Cited by PubMed Abstract: Heterobifunctional small-molecule degraders that induce protein degradation through ligase-mediated ubiquitination have shown considerable promise as a new pharmacological modality. However, we currently lack a detailed understanding of the molecular basis for target recruitment and selectivity, which is critically required to enable rational design of degraders. Here we utilize a comprehensive characterization of the ligand-dependent CRBN-BRD4 interaction to demonstrate that binding between proteins that have not evolved to interact is plastic. Multiple X-ray crystal structures show that plasticity results in several distinct low-energy binding conformations that are selectively bound by ligands. We demonstrate that computational protein-protein docking can reveal the underlying interprotein contacts and inform the design of a BRD4 selective degrader that can discriminate between highly homologous BET bromodomains. Our findings that plastic interprotein contacts confer selectivity for ligand-induced protein dimerization provide a conceptual framework for the development of heterobifunctional ligands. PubMed: 29892083DOI: 10.1038/s41589-018-0055-y PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.501 Å) |
Structure validation
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