Plasticity in binding confers selectivity in ligand-induced protein degradation

  • Nat Chem Biol. 2018 Jul;14(7):706-714. doi: 10.1038/s41589-018-0055-y.
Radosław P Nowak  1  2 ,  Stephen L DeAngelo  1 ,  Dennis Buckley  3  4 ,  Zhixiang He  1  2 ,  Katherine A Donovan  1  2 ,  Jian An  1  2 ,  Nozhat Safaee  1  2 ,  Mark P Jedrychowski  5  6 ,  Charles M Ponthier  1 ,  Mette Ishoey  3 ,  Tinghu Zhang  1  2 ,  Joseph D Mancias  5 ,  Nathanael S Gray  1  2 ,  James E Bradner  3  4 ,  Eric S Fischer  7  8
Affiliations
  • 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. [email protected].
  • 8. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. [email protected].
PMID: 29892083 DOI: 10.1038/s41589-018-0055-y
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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