6BN9

Crystal structure of DDB1-CRBN-BRD4(BD1) complex bound to dBET70 PROTAC

Summary for 6BN9

• Entry DOI: 10.2210/pdb6bn9/pdb
• Descriptor: DNA damage-binding protein 1,DNA damage-binding protein 1, Protein cereblon, Bromodomain-containing protein 4, ... (4 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: 164595.58

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

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: 29892083
DOI: 10.1038/s41589-018-0055-y

Experimental method

X-RAY DIFFRACTION (4.382 Å)