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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2021
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.
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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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