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Insights into the structure and function of the human organic anion transporter 1 in lipid bilayer membranes
The human SLC22A6/OAT1 plays an important role in the elimination of a broad range of endogenous substances and xenobiotics thus attracting attention from the pharmacological community. Furthermore, OAT1 is also involved in key physiological events such as the remote inter-organ communication. Despi...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9054760/ https://www.ncbi.nlm.nih.gov/pubmed/35488116 http://dx.doi.org/10.1038/s41598-022-10755-2 |
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author | Janaszkiewicz, Angelika Tóth, Ágota Faucher, Quentin Martin, Marving Chantemargue, Benjamin Barin-Le Guellec, Chantal Marquet, Pierre Di Meo, Florent |
author_facet | Janaszkiewicz, Angelika Tóth, Ágota Faucher, Quentin Martin, Marving Chantemargue, Benjamin Barin-Le Guellec, Chantal Marquet, Pierre Di Meo, Florent |
author_sort | Janaszkiewicz, Angelika |
collection | PubMed |
description | The human SLC22A6/OAT1 plays an important role in the elimination of a broad range of endogenous substances and xenobiotics thus attracting attention from the pharmacological community. Furthermore, OAT1 is also involved in key physiological events such as the remote inter-organ communication. Despite its significance, the knowledge about hOAT1 structure and the transport mechanism at the atomic level remains fragmented owing to the lack of resolved structures. By means of protein-threading modeling refined by μs-scaled Molecular Dynamics simulations, the present study provides the first robust model of hOAT1 in outward-facing conformation. Taking advantage of the AlphaFold 2 predicted structure of hOAT1 in inward-facing conformation, we here provide the essential structural and functional features comparing both states. The intracellular motifs conserved among Major Facilitator Superfamily members create a so-called “charge-relay system” that works as molecular switches modulating the conformation. The principal element of the event points at interactions of charged residues that appear crucial for the transporter dynamics and function. Moreover, hOAT1 model was embedded in different lipid bilayer membranes highlighting the crucial structural dependence on lipid-protein interactions. MD simulations supported the pivotal role of phosphatidylethanolamine components to the protein conformation stability. The present model is made available to decipher the impact of any observed polymorphism and mutation on drug transport as well as to understand substrate binding modes. |
format | Online Article Text |
id | pubmed-9054760 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-90547602022-05-01 Insights into the structure and function of the human organic anion transporter 1 in lipid bilayer membranes Janaszkiewicz, Angelika Tóth, Ágota Faucher, Quentin Martin, Marving Chantemargue, Benjamin Barin-Le Guellec, Chantal Marquet, Pierre Di Meo, Florent Sci Rep Article The human SLC22A6/OAT1 plays an important role in the elimination of a broad range of endogenous substances and xenobiotics thus attracting attention from the pharmacological community. Furthermore, OAT1 is also involved in key physiological events such as the remote inter-organ communication. Despite its significance, the knowledge about hOAT1 structure and the transport mechanism at the atomic level remains fragmented owing to the lack of resolved structures. By means of protein-threading modeling refined by μs-scaled Molecular Dynamics simulations, the present study provides the first robust model of hOAT1 in outward-facing conformation. Taking advantage of the AlphaFold 2 predicted structure of hOAT1 in inward-facing conformation, we here provide the essential structural and functional features comparing both states. The intracellular motifs conserved among Major Facilitator Superfamily members create a so-called “charge-relay system” that works as molecular switches modulating the conformation. The principal element of the event points at interactions of charged residues that appear crucial for the transporter dynamics and function. Moreover, hOAT1 model was embedded in different lipid bilayer membranes highlighting the crucial structural dependence on lipid-protein interactions. MD simulations supported the pivotal role of phosphatidylethanolamine components to the protein conformation stability. The present model is made available to decipher the impact of any observed polymorphism and mutation on drug transport as well as to understand substrate binding modes. Nature Publishing Group UK 2022-04-29 /pmc/articles/PMC9054760/ /pubmed/35488116 http://dx.doi.org/10.1038/s41598-022-10755-2 Text en © The Author(s) 2022 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Janaszkiewicz, Angelika Tóth, Ágota Faucher, Quentin Martin, Marving Chantemargue, Benjamin Barin-Le Guellec, Chantal Marquet, Pierre Di Meo, Florent Insights into the structure and function of the human organic anion transporter 1 in lipid bilayer membranes |
title | Insights into the structure and function of the human organic anion transporter 1 in lipid bilayer membranes |
title_full | Insights into the structure and function of the human organic anion transporter 1 in lipid bilayer membranes |
title_fullStr | Insights into the structure and function of the human organic anion transporter 1 in lipid bilayer membranes |
title_full_unstemmed | Insights into the structure and function of the human organic anion transporter 1 in lipid bilayer membranes |
title_short | Insights into the structure and function of the human organic anion transporter 1 in lipid bilayer membranes |
title_sort | insights into the structure and function of the human organic anion transporter 1 in lipid bilayer membranes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9054760/ https://www.ncbi.nlm.nih.gov/pubmed/35488116 http://dx.doi.org/10.1038/s41598-022-10755-2 |
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