Plasticity in binding confers selectivity in ligand-induced protein degradation
Nature chemical biology, 2018•nature.com
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 …
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 …
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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