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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Main Authors: 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
Format: Article
Language:English
Published: Nature Portfolio 2023-04-01
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.
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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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