Plasticity in binding confers selectivity in ligand-induced protein degradation.
Nat Chem Biol
; 14(7): 706-714, 2018 07.
Article
em En
| MEDLINE
| ID: mdl-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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Peptídeo Hidrolases
/
Talidomida
/
Tiofenos
/
Fatores de Transcrição
/
Proteínas Nucleares
/
Acetamidas
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Nat Chem Biol
Assunto da revista:
BIOLOGIA
/
QUIMICA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos