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A protein tertiary structure mimetic modulator of the Hippo signalling pathway
Transcription factors are key protein effectors in the regulation of gene transcription, and in many cases their activity is regulated via a complex network of protein–protein interactions (PPI). The chemical modulation of transcription factor activity is a long-standing goal in drug discovery but h...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591920/ https://www.ncbi.nlm.nih.gov/pubmed/33110077 http://dx.doi.org/10.1038/s41467-020-19224-8 |
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author | Adihou, Hélène Gopalakrishnan, Ranganath Förster, Tim Guéret, Stéphanie M. Gasper, Raphael Geschwindner, Stefan Carrillo García, Carmen Karatas, Hacer Pobbati, Ajaybabu V. Vazquez‐Chantada, Mercedes Davey, Paul Wassvik, Carola M. Pang, Jeremy Kah Sheng Soh, Boon Seng Hong, Wanjin Chiarparin, Elisabetta Schade, Dennis Plowright, Alleyn T. Valeur, Eric Lemurell, Malin Grossmann, Tom N. Waldmann, Herbert |
author_facet | Adihou, Hélène Gopalakrishnan, Ranganath Förster, Tim Guéret, Stéphanie M. Gasper, Raphael Geschwindner, Stefan Carrillo García, Carmen Karatas, Hacer Pobbati, Ajaybabu V. Vazquez‐Chantada, Mercedes Davey, Paul Wassvik, Carola M. Pang, Jeremy Kah Sheng Soh, Boon Seng Hong, Wanjin Chiarparin, Elisabetta Schade, Dennis Plowright, Alleyn T. Valeur, Eric Lemurell, Malin Grossmann, Tom N. Waldmann, Herbert |
author_sort | Adihou, Hélène |
collection | PubMed |
description | Transcription factors are key protein effectors in the regulation of gene transcription, and in many cases their activity is regulated via a complex network of protein–protein interactions (PPI). The chemical modulation of transcription factor activity is a long-standing goal in drug discovery but hampered by the difficulties associated with the targeting of PPIs, in particular when extended and flat protein interfaces are involved. Peptidomimetics have been applied to inhibit PPIs, however with variable success, as for certain interfaces the mimicry of a single secondary structure element is insufficient to obtain high binding affinities. Here, we describe the design and characterization of a stabilized protein tertiary structure that acts as an inhibitor of the interaction between the transcription factor TEAD and its co-repressor VGL4, both playing a central role in the Hippo signalling pathway. Modification of the inhibitor with a cell-penetrating entity yielded a cell-permeable proteomimetic that activates cell proliferation via regulation of the Hippo pathway, highlighting the potential of protein tertiary structure mimetics as an emerging class of PPI modulators. |
format | Online Article Text |
id | pubmed-7591920 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-75919202020-11-10 A protein tertiary structure mimetic modulator of the Hippo signalling pathway Adihou, Hélène Gopalakrishnan, Ranganath Förster, Tim Guéret, Stéphanie M. Gasper, Raphael Geschwindner, Stefan Carrillo García, Carmen Karatas, Hacer Pobbati, Ajaybabu V. Vazquez‐Chantada, Mercedes Davey, Paul Wassvik, Carola M. Pang, Jeremy Kah Sheng Soh, Boon Seng Hong, Wanjin Chiarparin, Elisabetta Schade, Dennis Plowright, Alleyn T. Valeur, Eric Lemurell, Malin Grossmann, Tom N. Waldmann, Herbert Nat Commun Article Transcription factors are key protein effectors in the regulation of gene transcription, and in many cases their activity is regulated via a complex network of protein–protein interactions (PPI). The chemical modulation of transcription factor activity is a long-standing goal in drug discovery but hampered by the difficulties associated with the targeting of PPIs, in particular when extended and flat protein interfaces are involved. Peptidomimetics have been applied to inhibit PPIs, however with variable success, as for certain interfaces the mimicry of a single secondary structure element is insufficient to obtain high binding affinities. Here, we describe the design and characterization of a stabilized protein tertiary structure that acts as an inhibitor of the interaction between the transcription factor TEAD and its co-repressor VGL4, both playing a central role in the Hippo signalling pathway. Modification of the inhibitor with a cell-penetrating entity yielded a cell-permeable proteomimetic that activates cell proliferation via regulation of the Hippo pathway, highlighting the potential of protein tertiary structure mimetics as an emerging class of PPI modulators. Nature Publishing Group UK 2020-10-27 /pmc/articles/PMC7591920/ /pubmed/33110077 http://dx.doi.org/10.1038/s41467-020-19224-8 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Adihou, Hélène Gopalakrishnan, Ranganath Förster, Tim Guéret, Stéphanie M. Gasper, Raphael Geschwindner, Stefan Carrillo García, Carmen Karatas, Hacer Pobbati, Ajaybabu V. Vazquez‐Chantada, Mercedes Davey, Paul Wassvik, Carola M. Pang, Jeremy Kah Sheng Soh, Boon Seng Hong, Wanjin Chiarparin, Elisabetta Schade, Dennis Plowright, Alleyn T. Valeur, Eric Lemurell, Malin Grossmann, Tom N. Waldmann, Herbert A protein tertiary structure mimetic modulator of the Hippo signalling pathway |
title | A protein tertiary structure mimetic modulator of the Hippo signalling pathway |
title_full | A protein tertiary structure mimetic modulator of the Hippo signalling pathway |
title_fullStr | A protein tertiary structure mimetic modulator of the Hippo signalling pathway |
title_full_unstemmed | A protein tertiary structure mimetic modulator of the Hippo signalling pathway |
title_short | A protein tertiary structure mimetic modulator of the Hippo signalling pathway |
title_sort | protein tertiary structure mimetic modulator of the hippo signalling pathway |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591920/ https://www.ncbi.nlm.nih.gov/pubmed/33110077 http://dx.doi.org/10.1038/s41467-020-19224-8 |
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