Target identification for small-molecule discovery in the FOXO3a tumor-suppressor pathway using a biodiverse peptide library.
Cell Chem Biol
; 28(11): 1602-1615.e9, 2021 11 18.
Article
em En
| MEDLINE
| ID: mdl-34111400
ABSTRACT
Genetic screening technologies to identify and validate macromolecular interactions (MMIs) essential for complex pathways remain an important unmet need for systems biology and therapeutics development. Here, we use a library of peptides from diverse prokaryal genomes to screen MMIs promoting the nuclear relocalization of Forkhead Box O3 (FOXO3a), a tumor suppressor more frequently inactivated by post-translational modification than mutation. A hit peptide engages the 14-3-3 family of signal regulators through a phosphorylation-dependent interaction, modulates FOXO3a-mediated transcription, and suppresses cancer cell growth. In a crystal structure, the hit peptide occupies the phosphopeptide-binding groove of 14-3-3ε in a conformation distinct from its natural peptide substrates. A biophysical screen identifies drug-like small molecules that displace the hit peptide from 14-3-3ε, providing starting points for structure-guided development. Our findings exemplify "protein interference," an approach using evolutionarily diverse, natural peptides to rapidly identify, validate, and develop chemical probes against MMIs essential for complex cellular phenotypes.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Bibliotecas de Moléculas Pequenas
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Descoberta de Drogas
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Proteína Forkhead Box O3
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article