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Target identification for small-molecule discovery in the FOXO3a tumor-suppressor pathway using a biodiverse peptide library
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 nu...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8610377/ https://www.ncbi.nlm.nih.gov/pubmed/34111400 http://dx.doi.org/10.1016/j.chembiol.2021.05.009 |
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author | Emery, Amy Hardwick, Bryn S. Crooks, Alex T. Milech, Nadia Watt, Paul M. Mithra, Chandan Kumar, Vikrant Giridharan, Saranya Sadasivam, Gayathri Mathivanan, Subashini Sudhakar, Sneha Bairy, Sneha Bharatham, Kavitha Hurakadli, Manjunath A. Prasad, Thazhe K. Kamariah, Neelagandan Muellner, Markus Coelho, Miguel Torrance, Christopher J. McKenzie, Grahame J. Venkitaraman, Ashok R. |
author_facet | Emery, Amy Hardwick, Bryn S. Crooks, Alex T. Milech, Nadia Watt, Paul M. Mithra, Chandan Kumar, Vikrant Giridharan, Saranya Sadasivam, Gayathri Mathivanan, Subashini Sudhakar, Sneha Bairy, Sneha Bharatham, Kavitha Hurakadli, Manjunath A. Prasad, Thazhe K. Kamariah, Neelagandan Muellner, Markus Coelho, Miguel Torrance, Christopher J. McKenzie, Grahame J. Venkitaraman, Ashok R. |
author_sort | Emery, Amy |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8610377 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-86103772021-11-29 Target identification for small-molecule discovery in the FOXO3a tumor-suppressor pathway using a biodiverse peptide library Emery, Amy Hardwick, Bryn S. Crooks, Alex T. Milech, Nadia Watt, Paul M. Mithra, Chandan Kumar, Vikrant Giridharan, Saranya Sadasivam, Gayathri Mathivanan, Subashini Sudhakar, Sneha Bairy, Sneha Bharatham, Kavitha Hurakadli, Manjunath A. Prasad, Thazhe K. Kamariah, Neelagandan Muellner, Markus Coelho, Miguel Torrance, Christopher J. McKenzie, Grahame J. Venkitaraman, Ashok R. Cell Chem Biol Article 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. Cell Press 2021-11-18 /pmc/articles/PMC8610377/ /pubmed/34111400 http://dx.doi.org/10.1016/j.chembiol.2021.05.009 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Emery, Amy Hardwick, Bryn S. Crooks, Alex T. Milech, Nadia Watt, Paul M. Mithra, Chandan Kumar, Vikrant Giridharan, Saranya Sadasivam, Gayathri Mathivanan, Subashini Sudhakar, Sneha Bairy, Sneha Bharatham, Kavitha Hurakadli, Manjunath A. Prasad, Thazhe K. Kamariah, Neelagandan Muellner, Markus Coelho, Miguel Torrance, Christopher J. McKenzie, Grahame J. Venkitaraman, Ashok R. Target identification for small-molecule discovery in the FOXO3a tumor-suppressor pathway using a biodiverse peptide library |
title | Target identification for small-molecule discovery in the FOXO3a tumor-suppressor pathway using a biodiverse peptide library |
title_full | Target identification for small-molecule discovery in the FOXO3a tumor-suppressor pathway using a biodiverse peptide library |
title_fullStr | Target identification for small-molecule discovery in the FOXO3a tumor-suppressor pathway using a biodiverse peptide library |
title_full_unstemmed | Target identification for small-molecule discovery in the FOXO3a tumor-suppressor pathway using a biodiverse peptide library |
title_short | Target identification for small-molecule discovery in the FOXO3a tumor-suppressor pathway using a biodiverse peptide library |
title_sort | target identification for small-molecule discovery in the foxo3a tumor-suppressor pathway using a biodiverse peptide library |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8610377/ https://www.ncbi.nlm.nih.gov/pubmed/34111400 http://dx.doi.org/10.1016/j.chembiol.2021.05.009 |
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