2. Academic Validation
  3. Plasticity in binding confers selectivity in ligand-induced protein degradation

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

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. eric_fischer@dfci.harvard.edu.
  • 8 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. eric_fischer@dfci.harvard.edu.
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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