Target identification for small-molecule discovery in the FOXO3a tumor-suppressor pathway using a biodiverse peptide library
| العنوان: | Target identification for small-molecule discovery in the FOXO3a tumor-suppressor pathway using a biodiverse peptide library |
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| المؤلفون: | Vikrant Kumar, Bryn Hardwick, Saranya Giridharan, Sneha Sudhakar, Markus Muellner, Manjunath A. Hurakadli, Ashok R. Venkitaraman, Gayathri Sadasivam, T.K. Prasad, Neelagandan Kamariah, Grahame J. McKenzie, Alex T. Crooks, Subashini Mathivanan, Paul M. Watt, Miguel Coelho, Sneha Bairy, Nadia Milech, Chandan Mithra, Christopher J. Torrance, Amy Emery, Kavitha Bharatham |
| المصدر: | Cell Chemical Biology |
| بيانات النشر: | Elsevier BV, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Phenotypic screening, Systems biology, Clinical Biochemistry, Peptide, Computational biology, Biology, medicine.disease_cause, 01 natural sciences, Biochemistry, Article, Protein–protein interaction, law.invention, Small Molecule Libraries, protein-protein interaction, Peptide Library, target identification, law, Drug Discovery, medicine, Humans, Genes, Tumor Suppressor, Phosphorylation, FOXO3a, lead discovery, Peptide library, Molecular Biology, Cells, Cultured, 14-3-3, Pharmacology, chemistry.chemical_classification, Mutation, 010405 organic chemistry, Forkhead Box Protein O3, phenotypic screening, Small molecule, 0104 chemical sciences, prokaryal genomes, target validation, chemistry, bioactive peptide, Molecular Medicine, Suppressor, Female, protein interference |
| الوصف: | Summary 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. Graphical abstract Highlights • We describe protein interference, an approach to identify and validate new drug targets • A genetic screen identifies a protein interference probe inducing FOXO3a reactivation • The probe defines a druggable binding site in the 14-3-3 signal regulator family • We illustrate a workflow to parse complex cellular pathways for new drug targets Emery et al. describe “protein interference,” an approach to identify and validate new drug targets using structurally diverse natural peptides in genetic screens for cellular phenotypes. They discover a druggable site in 14-3-3 proteins that reactivates FOXO3a, and validate its structural features and biological activity. |
| تدمد: | 2451-9456 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::82261f81e78bea18e12f385b6c100941 https://doi.org/10.1016/j.chembiol.2021.05.009 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....82261f81e78bea18e12f385b6c100941 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 24519456 |
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