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A rational blueprint for the design of chemically-controlled protein switches
Small-molecule responsive protein switches are crucial components to control synthetic cellular activities. However, the repertoire of small-molecule protein switches is insufficient for many applications, including those in the translational spaces, where properties such as safety, immunogenicity,...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486872/ https://www.ncbi.nlm.nih.gov/pubmed/34599176 http://dx.doi.org/10.1038/s41467-021-25735-9 |
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author | Shui, Sailan Gainza, Pablo Scheller, Leo Yang, Che Kurumida, Yoichi Rosset, Stéphane Georgeon, Sandrine Di Roberto, Raphaël B. Castellanos-Rueda, Rocío Reddy, Sai T. Correia, Bruno E. |
author_facet | Shui, Sailan Gainza, Pablo Scheller, Leo Yang, Che Kurumida, Yoichi Rosset, Stéphane Georgeon, Sandrine Di Roberto, Raphaël B. Castellanos-Rueda, Rocío Reddy, Sai T. Correia, Bruno E. |
author_sort | Shui, Sailan |
collection | PubMed |
description | Small-molecule responsive protein switches are crucial components to control synthetic cellular activities. However, the repertoire of small-molecule protein switches is insufficient for many applications, including those in the translational spaces, where properties such as safety, immunogenicity, drug half-life, and drug side-effects are critical. Here, we present a computational protein design strategy to repurpose drug-inhibited protein-protein interactions as OFF- and ON-switches. The designed binders and drug-receptors form chemically-disruptable heterodimers (CDH) which dissociate in the presence of small molecules. To design ON-switches, we converted the CDHs into a multi-domain architecture which we refer to as activation by inhibitor release switches (AIR) that incorporate a rationally designed drug-insensitive receptor protein. CDHs and AIRs showed excellent performance as drug responsive switches to control combinations of synthetic circuits in mammalian cells. This approach effectively expands the chemical space and logic responses in living cells and provides a blueprint to develop new ON- and OFF-switches. |
format | Online Article Text |
id | pubmed-8486872 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-84868722021-10-07 A rational blueprint for the design of chemically-controlled protein switches Shui, Sailan Gainza, Pablo Scheller, Leo Yang, Che Kurumida, Yoichi Rosset, Stéphane Georgeon, Sandrine Di Roberto, Raphaël B. Castellanos-Rueda, Rocío Reddy, Sai T. Correia, Bruno E. Nat Commun Article Small-molecule responsive protein switches are crucial components to control synthetic cellular activities. However, the repertoire of small-molecule protein switches is insufficient for many applications, including those in the translational spaces, where properties such as safety, immunogenicity, drug half-life, and drug side-effects are critical. Here, we present a computational protein design strategy to repurpose drug-inhibited protein-protein interactions as OFF- and ON-switches. The designed binders and drug-receptors form chemically-disruptable heterodimers (CDH) which dissociate in the presence of small molecules. To design ON-switches, we converted the CDHs into a multi-domain architecture which we refer to as activation by inhibitor release switches (AIR) that incorporate a rationally designed drug-insensitive receptor protein. CDHs and AIRs showed excellent performance as drug responsive switches to control combinations of synthetic circuits in mammalian cells. This approach effectively expands the chemical space and logic responses in living cells and provides a blueprint to develop new ON- and OFF-switches. Nature Publishing Group UK 2021-10-01 /pmc/articles/PMC8486872/ /pubmed/34599176 http://dx.doi.org/10.1038/s41467-021-25735-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Shui, Sailan Gainza, Pablo Scheller, Leo Yang, Che Kurumida, Yoichi Rosset, Stéphane Georgeon, Sandrine Di Roberto, Raphaël B. Castellanos-Rueda, Rocío Reddy, Sai T. Correia, Bruno E. A rational blueprint for the design of chemically-controlled protein switches |
title | A rational blueprint for the design of chemically-controlled protein switches |
title_full | A rational blueprint for the design of chemically-controlled protein switches |
title_fullStr | A rational blueprint for the design of chemically-controlled protein switches |
title_full_unstemmed | A rational blueprint for the design of chemically-controlled protein switches |
title_short | A rational blueprint for the design of chemically-controlled protein switches |
title_sort | rational blueprint for the design of chemically-controlled protein switches |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486872/ https://www.ncbi.nlm.nih.gov/pubmed/34599176 http://dx.doi.org/10.1038/s41467-021-25735-9 |
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