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Computational Analysis of Histamine Protonation Effects on H(1)R Binding
Despite numerous studies investigating histamine and its receptors, the impact of histamine protonation states on binding to the histamine H [Formula: see text]-receptor (H [Formula: see text] R) has remained elusive. Therefore, we assessed the influence of different histamine tautomers ([Formula: s...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10180022/ https://www.ncbi.nlm.nih.gov/pubmed/37175183 http://dx.doi.org/10.3390/molecules28093774 |
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author | Conrad, Marcus Horn, Anselm H. C. Sticht, Heinrich |
author_facet | Conrad, Marcus Horn, Anselm H. C. Sticht, Heinrich |
author_sort | Conrad, Marcus |
collection | PubMed |
description | Despite numerous studies investigating histamine and its receptors, the impact of histamine protonation states on binding to the histamine H [Formula: see text]-receptor (H [Formula: see text] R) has remained elusive. Therefore, we assessed the influence of different histamine tautomers ([Formula: see text]-tautomer, [Formula: see text]-tautomer) and charge states (mono- vs. dicationic) on the interaction with the ternary histamine-H [Formula: see text] R-G(q) complex. In atomistic molecular dynamics simulations, the [Formula: see text]-tautomer formed stable interactions with the receptor, while the [Formula: see text]-tautomer induced a rotation of the histamine ring by 180° and formed only weaker hydrogen bonding interactions. This suggests that the [Formula: see text]-tautomer is more relevant for stabilization of the active ternary histamine-H [Formula: see text] R-G(q) complex. In addition to the two monocationic tautomers, the binding of dicationic histamine was investigated, whose interaction with the H [Formula: see text] R had been observed in a previous experimental study. Our simulations showed that the dication is less compatible with the ternary histamine-H [Formula: see text] R-G(q) complex and rather induces an inactive conformation in the absence of the G(q) protein. Our data thus indicate that the charge state of histamine critically affects its interactions with the H [Formula: see text] R. Ultimately these findings might have implications for the future development of new ligands that stabilize distinct H [Formula: see text] R activation states. |
format | Online Article Text |
id | pubmed-10180022 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-101800222023-05-13 Computational Analysis of Histamine Protonation Effects on H(1)R Binding Conrad, Marcus Horn, Anselm H. C. Sticht, Heinrich Molecules Article Despite numerous studies investigating histamine and its receptors, the impact of histamine protonation states on binding to the histamine H [Formula: see text]-receptor (H [Formula: see text] R) has remained elusive. Therefore, we assessed the influence of different histamine tautomers ([Formula: see text]-tautomer, [Formula: see text]-tautomer) and charge states (mono- vs. dicationic) on the interaction with the ternary histamine-H [Formula: see text] R-G(q) complex. In atomistic molecular dynamics simulations, the [Formula: see text]-tautomer formed stable interactions with the receptor, while the [Formula: see text]-tautomer induced a rotation of the histamine ring by 180° and formed only weaker hydrogen bonding interactions. This suggests that the [Formula: see text]-tautomer is more relevant for stabilization of the active ternary histamine-H [Formula: see text] R-G(q) complex. In addition to the two monocationic tautomers, the binding of dicationic histamine was investigated, whose interaction with the H [Formula: see text] R had been observed in a previous experimental study. Our simulations showed that the dication is less compatible with the ternary histamine-H [Formula: see text] R-G(q) complex and rather induces an inactive conformation in the absence of the G(q) protein. Our data thus indicate that the charge state of histamine critically affects its interactions with the H [Formula: see text] R. Ultimately these findings might have implications for the future development of new ligands that stabilize distinct H [Formula: see text] R activation states. MDPI 2023-04-27 /pmc/articles/PMC10180022/ /pubmed/37175183 http://dx.doi.org/10.3390/molecules28093774 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Conrad, Marcus Horn, Anselm H. C. Sticht, Heinrich Computational Analysis of Histamine Protonation Effects on H(1)R Binding |
title | Computational Analysis of Histamine Protonation Effects on H(1)R Binding |
title_full | Computational Analysis of Histamine Protonation Effects on H(1)R Binding |
title_fullStr | Computational Analysis of Histamine Protonation Effects on H(1)R Binding |
title_full_unstemmed | Computational Analysis of Histamine Protonation Effects on H(1)R Binding |
title_short | Computational Analysis of Histamine Protonation Effects on H(1)R Binding |
title_sort | computational analysis of histamine protonation effects on h(1)r binding |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10180022/ https://www.ncbi.nlm.nih.gov/pubmed/37175183 http://dx.doi.org/10.3390/molecules28093774 |
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