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Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT(1A) Receptor

G‐protein‐coupled receptors (GPCRs) are involved in a wide range of physiological processes, and they have attracted considerable attention as important targets for developing new medicines. A central and largely unresolved question in drug discovery, which is especially relevant to GPCRs, concerns...

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Autores principales: Yuan, Shuguang, Peng, Qian, Palczewski, Krzysztof, Vogel, Horst, Filipek, Slawomir
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957245/
https://www.ncbi.nlm.nih.gov/pubmed/27244650
http://dx.doi.org/10.1002/anie.201603766
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author Yuan, Shuguang
Peng, Qian
Palczewski, Krzysztof
Vogel, Horst
Filipek, Slawomir
author_facet Yuan, Shuguang
Peng, Qian
Palczewski, Krzysztof
Vogel, Horst
Filipek, Slawomir
author_sort Yuan, Shuguang
collection PubMed
description G‐protein‐coupled receptors (GPCRs) are involved in a wide range of physiological processes, and they have attracted considerable attention as important targets for developing new medicines. A central and largely unresolved question in drug discovery, which is especially relevant to GPCRs, concerns ligand selectivity: Why do certain molecules act as activators (agonists) whereas others, with nearly identical structures, act as blockers (antagonists) of GPCRs? To address this question, we employed all‐atom, long‐timescale molecular dynamics simulations to investigate how two diastereomers (epimers) of dihydrofuroaporphine bind to the serotonin 5‐HT(1A) receptor and exert opposite effects. By using molecular interaction fingerprints, we discovered that the agonist could mobilize nearby amino acid residues to act as molecular switches for the formation of a continuous water channel. In contrast, the antagonist epimer remained firmly stabilized in the binding pocket.
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spelling pubmed-49572452016-07-22 Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT(1A) Receptor Yuan, Shuguang Peng, Qian Palczewski, Krzysztof Vogel, Horst Filipek, Slawomir Angew Chem Int Ed Engl Communications G‐protein‐coupled receptors (GPCRs) are involved in a wide range of physiological processes, and they have attracted considerable attention as important targets for developing new medicines. A central and largely unresolved question in drug discovery, which is especially relevant to GPCRs, concerns ligand selectivity: Why do certain molecules act as activators (agonists) whereas others, with nearly identical structures, act as blockers (antagonists) of GPCRs? To address this question, we employed all‐atom, long‐timescale molecular dynamics simulations to investigate how two diastereomers (epimers) of dihydrofuroaporphine bind to the serotonin 5‐HT(1A) receptor and exert opposite effects. By using molecular interaction fingerprints, we discovered that the agonist could mobilize nearby amino acid residues to act as molecular switches for the formation of a continuous water channel. In contrast, the antagonist epimer remained firmly stabilized in the binding pocket. John Wiley and Sons Inc. 2016-05-31 2016-07-18 /pmc/articles/PMC4957245/ /pubmed/27244650 http://dx.doi.org/10.1002/anie.201603766 Text en © 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Communications
Yuan, Shuguang
Peng, Qian
Palczewski, Krzysztof
Vogel, Horst
Filipek, Slawomir
Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT(1A) Receptor
title Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT(1A) Receptor
title_full Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT(1A) Receptor
title_fullStr Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT(1A) Receptor
title_full_unstemmed Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT(1A) Receptor
title_short Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT(1A) Receptor
title_sort mechanistic studies on the stereoselectivity of the serotonin 5‐ht(1a) receptor
topic Communications
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957245/
https://www.ncbi.nlm.nih.gov/pubmed/27244650
http://dx.doi.org/10.1002/anie.201603766
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