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Turning up the heat mimics allosteric signaling in imidazole-glycerol phosphate synthase
Allosteric drugs have the potential to revolutionize biomedicine due to their enhanced selectivity and protection against overdosage. However, we need to better understand allosteric mechanisms in order to fully harness their potential in drug discovery. In this study, molecular dynamics simulations...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10115891/ https://www.ncbi.nlm.nih.gov/pubmed/37076500 http://dx.doi.org/10.1038/s41467-023-37956-1 |
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author | Maschietto, Federica Morzan, Uriel N. Tofoleanu, Florentina Gheeraert, Aria Chaudhuri, Apala Kyro, Gregory W. Nekrasov, Peter Brooks, Bernard Loria, J. Patrick Rivalta, Ivan Batista, Victor S. |
author_facet | Maschietto, Federica Morzan, Uriel N. Tofoleanu, Florentina Gheeraert, Aria Chaudhuri, Apala Kyro, Gregory W. Nekrasov, Peter Brooks, Bernard Loria, J. Patrick Rivalta, Ivan Batista, Victor S. |
author_sort | Maschietto, Federica |
collection | PubMed |
description | Allosteric drugs have the potential to revolutionize biomedicine due to their enhanced selectivity and protection against overdosage. However, we need to better understand allosteric mechanisms in order to fully harness their potential in drug discovery. In this study, molecular dynamics simulations and nuclear magnetic resonance spectroscopy are used to investigate how increases in temperature affect allostery in imidazole glycerol phosphate synthase. Results demonstrate that temperature increase triggers a cascade of local amino acid-to-amino acid dynamics that remarkably resembles the allosteric activation that takes place upon effector binding. The differences in the allosteric response elicited by temperature increase as opposed to effector binding are conditional to the alterations of collective motions induced by either mode of activation. This work provides an atomistic picture of temperature-dependent allostery, which could be harnessed to more precisely control enzyme function. |
format | Online Article Text |
id | pubmed-10115891 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-101158912023-04-21 Turning up the heat mimics allosteric signaling in imidazole-glycerol phosphate synthase Maschietto, Federica Morzan, Uriel N. Tofoleanu, Florentina Gheeraert, Aria Chaudhuri, Apala Kyro, Gregory W. Nekrasov, Peter Brooks, Bernard Loria, J. Patrick Rivalta, Ivan Batista, Victor S. Nat Commun Article Allosteric drugs have the potential to revolutionize biomedicine due to their enhanced selectivity and protection against overdosage. However, we need to better understand allosteric mechanisms in order to fully harness their potential in drug discovery. In this study, molecular dynamics simulations and nuclear magnetic resonance spectroscopy are used to investigate how increases in temperature affect allostery in imidazole glycerol phosphate synthase. Results demonstrate that temperature increase triggers a cascade of local amino acid-to-amino acid dynamics that remarkably resembles the allosteric activation that takes place upon effector binding. The differences in the allosteric response elicited by temperature increase as opposed to effector binding are conditional to the alterations of collective motions induced by either mode of activation. This work provides an atomistic picture of temperature-dependent allostery, which could be harnessed to more precisely control enzyme function. Nature Publishing Group UK 2023-04-19 /pmc/articles/PMC10115891/ /pubmed/37076500 http://dx.doi.org/10.1038/s41467-023-37956-1 Text en © The Author(s) 2023, corrected publication 2023 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 Maschietto, Federica Morzan, Uriel N. Tofoleanu, Florentina Gheeraert, Aria Chaudhuri, Apala Kyro, Gregory W. Nekrasov, Peter Brooks, Bernard Loria, J. Patrick Rivalta, Ivan Batista, Victor S. Turning up the heat mimics allosteric signaling in imidazole-glycerol phosphate synthase |
title | Turning up the heat mimics allosteric signaling in imidazole-glycerol phosphate synthase |
title_full | Turning up the heat mimics allosteric signaling in imidazole-glycerol phosphate synthase |
title_fullStr | Turning up the heat mimics allosteric signaling in imidazole-glycerol phosphate synthase |
title_full_unstemmed | Turning up the heat mimics allosteric signaling in imidazole-glycerol phosphate synthase |
title_short | Turning up the heat mimics allosteric signaling in imidazole-glycerol phosphate synthase |
title_sort | turning up the heat mimics allosteric signaling in imidazole-glycerol phosphate synthase |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10115891/ https://www.ncbi.nlm.nih.gov/pubmed/37076500 http://dx.doi.org/10.1038/s41467-023-37956-1 |
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