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

<div class='caption-title'>Structure of the DDB1ΔB-CRBN-dBET23-BRD4BD1 complex</div>
<div class='caption-title'>Degrader mediated BRD4 recruitment is governed by negative cooperativity</div>
<div class='caption-title'>Quantitative assessment of cellular degradation for BRD4BD1 and BRD4BD2</div>
Nowak RP, DeAngelo SL, Buckley D, He Z, Donovan KA, An J, Safaee N, Jedrychowski MP, Ponthier CM, Ishoey M, Zhang T, Mancias JD, Gray NS, Bradner JE, Fischer ES
OpenAccess logo Nat Chem Biol 14 706-714 (2018)
Related entries: 6bn7, 6bn8, 6bn9, 6boy

Cited: 204 times
EuropePMC logo PMID: 29892083

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.

Reviews - 6bnb mentioned but not cited (2)

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Reviews citing this publication (70)

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