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Plasticity in binding confers selectivity in ligand-induced protein degradation

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

Authors: Radoslaw P. Nowak (University of Oxford) , Stephen L. Deangelo (Dana-Farber Cancer Institute) , Dennis Buckley (Dana-Farber Cancer Institute) , Zhixiang He (Dana-Farber Cancer Institute) , Katherine A. Donovan (Dana-Farber Cancer Institute) , Jian An (Dana-Farber Cancer Institute) , Nozhat Safaee (Dana-Farber Cancer Institute) , Mark P. Jedrychowski (Dana-Farber Cancer Institute) , Charles M. Ponthier (Dana-Farber Cancer Institute) , Mette Ishoey (Dana-Farber Cancer Institute) , Tinghu Zhang (Dana-Farber Cancer Institute) , Joseph D. Mancias (Dana-Farber Cancer Institute) , Nathanael S. Gray (Dana-Farber Cancer Institute) , James E. Bradner (Dana-Farber Cancer Institute) , Eric S. Fischer (Dana-Farber Cancer Institute)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Chemical Biology , VOL 14 , PAGES 706 - 714

State: Published (Approved)
Published: June 2018

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.

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)