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

Publication Type:

Journal Article

Source:

Nat Chem Biol (2018)

Abstract:

<p>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.</p>

PDB: 
DDB1∆B-CRBN-dBET23-BRD4BD1 (6BN7), DDB1∆B-CRBN-dBET6-BRD4BD1 (6BOY), DDB1∆B-CRBN-dBET70-BRD4BD1 (6BN9), DDB1∆B-CRBN-dBET55-BRD4BD1 (6BN8), DDB1∆B-CRBN-dBET57-BRD4BD1 (6BNB)
Detector: 
PILATUS
EIGER
Beamline: 
24-ID-C
24-ID-E