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The transport pathway in the ABCG2 protein and its regulation revealed by molecular dynamics simulations

Atomic-level structural insight on the human ABCG2 membrane protein, a pharmacologically important transporter, has been recently revealed by several key papers. In spite of the wealth of structural data, the pathway of transmembrane movement for the large variety of structurally different ABCG2 sub...

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Autores principales: Nagy, Tamás, Tóth, Ágota, Telbisz, Ágnes, Sarkadi, Balázs, Tordai, Hedvig, Tordai, Attila, Hegedűs, Tamás
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966132/
https://www.ncbi.nlm.nih.gov/pubmed/32979053
http://dx.doi.org/10.1007/s00018-020-03651-3
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author Nagy, Tamás
Tóth, Ágota
Telbisz, Ágnes
Sarkadi, Balázs
Tordai, Hedvig
Tordai, Attila
Hegedűs, Tamás
author_facet Nagy, Tamás
Tóth, Ágota
Telbisz, Ágnes
Sarkadi, Balázs
Tordai, Hedvig
Tordai, Attila
Hegedűs, Tamás
author_sort Nagy, Tamás
collection PubMed
description Atomic-level structural insight on the human ABCG2 membrane protein, a pharmacologically important transporter, has been recently revealed by several key papers. In spite of the wealth of structural data, the pathway of transmembrane movement for the large variety of structurally different ABCG2 substrates and the physiological lipid regulation of the transporter has not been elucidated. The complex molecular dynamics simulations presented here may provide a breakthrough in understanding the steps of the substrate transport process and its regulation by cholesterol. Our analysis revealed drug binding cavities other than the central binding site and delineated a putative dynamic transport pathway for substrates with variable structures. We found that membrane cholesterol accelerated drug transport by promoting the closure of cytoplasmic protein regions. Since ABCG2 is present in all major biological barriers and drug-metabolizing organs, influences the pharmacokinetics of numerous clinically applied drugs, and plays a key role in uric acid extrusion, this information may significantly promote a reliable prediction of clinically important substrate characteristics and drug-drug interactions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00018-020-03651-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-79661322021-04-01 The transport pathway in the ABCG2 protein and its regulation revealed by molecular dynamics simulations Nagy, Tamás Tóth, Ágota Telbisz, Ágnes Sarkadi, Balázs Tordai, Hedvig Tordai, Attila Hegedűs, Tamás Cell Mol Life Sci Original Article Atomic-level structural insight on the human ABCG2 membrane protein, a pharmacologically important transporter, has been recently revealed by several key papers. In spite of the wealth of structural data, the pathway of transmembrane movement for the large variety of structurally different ABCG2 substrates and the physiological lipid regulation of the transporter has not been elucidated. The complex molecular dynamics simulations presented here may provide a breakthrough in understanding the steps of the substrate transport process and its regulation by cholesterol. Our analysis revealed drug binding cavities other than the central binding site and delineated a putative dynamic transport pathway for substrates with variable structures. We found that membrane cholesterol accelerated drug transport by promoting the closure of cytoplasmic protein regions. Since ABCG2 is present in all major biological barriers and drug-metabolizing organs, influences the pharmacokinetics of numerous clinically applied drugs, and plays a key role in uric acid extrusion, this information may significantly promote a reliable prediction of clinically important substrate characteristics and drug-drug interactions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00018-020-03651-3) contains supplementary material, which is available to authorized users. Springer International Publishing 2020-09-26 2021 /pmc/articles/PMC7966132/ /pubmed/32979053 http://dx.doi.org/10.1007/s00018-020-03651-3 Text en © The Author(s) 2020 Open AccessThis 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/.
spellingShingle Original Article
Nagy, Tamás
Tóth, Ágota
Telbisz, Ágnes
Sarkadi, Balázs
Tordai, Hedvig
Tordai, Attila
Hegedűs, Tamás
The transport pathway in the ABCG2 protein and its regulation revealed by molecular dynamics simulations
title The transport pathway in the ABCG2 protein and its regulation revealed by molecular dynamics simulations
title_full The transport pathway in the ABCG2 protein and its regulation revealed by molecular dynamics simulations
title_fullStr The transport pathway in the ABCG2 protein and its regulation revealed by molecular dynamics simulations
title_full_unstemmed The transport pathway in the ABCG2 protein and its regulation revealed by molecular dynamics simulations
title_short The transport pathway in the ABCG2 protein and its regulation revealed by molecular dynamics simulations
title_sort transport pathway in the abcg2 protein and its regulation revealed by molecular dynamics simulations
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966132/
https://www.ncbi.nlm.nih.gov/pubmed/32979053
http://dx.doi.org/10.1007/s00018-020-03651-3
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