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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,...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
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.
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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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