Turning up the heat mimics allosteric signaling in imidazole-glycerol phosphate synthase
Abstract 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 si...
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Nature Portfolio
2023-04-01
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Series: | Nature Communications |
Online Access: | https://doi.org/10.1038/s41467-023-37956-1 |
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author | Federica Maschietto Uriel N. Morzan Florentina Tofoleanu Aria Gheeraert Apala Chaudhuri Gregory W. Kyro Peter Nekrasov Bernard Brooks J. Patrick Loria Ivan Rivalta Victor S. Batista |
author_facet | Federica Maschietto Uriel N. Morzan Florentina Tofoleanu Aria Gheeraert Apala Chaudhuri Gregory W. Kyro Peter Nekrasov Bernard Brooks J. Patrick Loria Ivan Rivalta Victor S. Batista |
author_sort | Federica Maschietto |
collection | DOAJ |
description | Abstract 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. |
first_indexed | 2024-04-09T14:01:30Z |
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id | doaj.art-c96d714daf7444efb6b389b4fdae9c83 |
institution | Directory Open Access Journal |
issn | 2041-1723 |
language | English |
last_indexed | 2024-04-09T14:01:30Z |
publishDate | 2023-04-01 |
publisher | Nature Portfolio |
record_format | Article |
series | Nature Communications |
spelling | doaj.art-c96d714daf7444efb6b389b4fdae9c832023-05-07T11:16:56ZengNature PortfolioNature Communications2041-17232023-04-0114111310.1038/s41467-023-37956-1Turning up the heat mimics allosteric signaling in imidazole-glycerol phosphate synthaseFederica Maschietto0Uriel N. Morzan1Florentina Tofoleanu2Aria Gheeraert3Apala Chaudhuri4Gregory W. Kyro5Peter Nekrasov6Bernard Brooks7J. Patrick Loria8Ivan Rivalta9Victor S. Batista10Department of Chemistry, Yale UniversityInternational Center for Theoretical PhysicsDepartment of Chemistry, Yale UniversityENSL, CNRS, Laboratoire de Chimie UMR 5182Department of Molecular Biophysics and Biochemistry, Yale UniversityDepartment of Chemistry, Yale UniversityDepartment of Chemistry, Yale UniversityLaboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of HealthDepartment of Chemistry, Yale UniversityENSL, CNRS, Laboratoire de Chimie UMR 5182Department of Chemistry, Yale UniversityAbstract 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.https://doi.org/10.1038/s41467-023-37956-1 |
spellingShingle | Federica Maschietto Uriel N. Morzan Florentina Tofoleanu Aria Gheeraert Apala Chaudhuri Gregory W. Kyro Peter Nekrasov Bernard Brooks J. Patrick Loria Ivan Rivalta Victor S. Batista Turning up the heat mimics allosteric signaling in imidazole-glycerol phosphate synthase Nature Communications |
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 |
url | https://doi.org/10.1038/s41467-023-37956-1 |
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