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Nat Chem Biol. 2018 Jul;14(7):706-714. doi: 10.1038/s41589-018-0055-y. Epub 2018 Jun 11.

Plasticity in binding confers selectivity in ligand-induced protein degradation.

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
2
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
3
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
4
Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
5
Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
6
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
7
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. eric_fischer@dfci.harvard.edu.
8
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. eric_fischer@dfci.harvard.edu.

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.

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