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The structure of the human ABC transporter ABCG2 reveals a novel mechanism for drug extrusion
The human ABC transporter ABCG2 (Breast Cancer Resistance Protein, BCRP) is implicated in anticancer resistance, in detoxification across barriers and linked to gout. Here, we generate a novel atomic model of ABCG2 using the crystal structure of ABCG5/G8. Extensive mutagenesis verifies the structure...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653816/ https://www.ncbi.nlm.nih.gov/pubmed/29061978 http://dx.doi.org/10.1038/s41598-017-11794-w |
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author | Khunweeraphong, Narakorn Stockner, Thomas Kuchler, Karl |
author_facet | Khunweeraphong, Narakorn Stockner, Thomas Kuchler, Karl |
author_sort | Khunweeraphong, Narakorn |
collection | PubMed |
description | The human ABC transporter ABCG2 (Breast Cancer Resistance Protein, BCRP) is implicated in anticancer resistance, in detoxification across barriers and linked to gout. Here, we generate a novel atomic model of ABCG2 using the crystal structure of ABCG5/G8. Extensive mutagenesis verifies the structure, disclosing hitherto unrecognized essential residues and domains in the homodimeric ABCG2 transporter. The elbow helix, the first intracellular loop (ICL1) and the nucleotide-binding domain (NBD) constitute pivotal elements of the architecture building the transmission interface that borders a central cavity which acts as a drug trap. The transmission interface is stabilized by salt-bridge interactions between the elbow helix and ICL1, as well as within ICL1, which is essential to control the conformational switch of ABCG2 to the outward-open drug-releasing conformation. Importantly, we propose that ICL1 operates like a molecular spring that holds the NBD dimer close to the membrane, thereby enabling efficient coupling of ATP hydrolysis during the catalytic cycle. These novel mechanistic data open new opportunities to therapeutically target ABCG2 in the context of related diseases. |
format | Online Article Text |
id | pubmed-5653816 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-56538162017-11-08 The structure of the human ABC transporter ABCG2 reveals a novel mechanism for drug extrusion Khunweeraphong, Narakorn Stockner, Thomas Kuchler, Karl Sci Rep Article The human ABC transporter ABCG2 (Breast Cancer Resistance Protein, BCRP) is implicated in anticancer resistance, in detoxification across barriers and linked to gout. Here, we generate a novel atomic model of ABCG2 using the crystal structure of ABCG5/G8. Extensive mutagenesis verifies the structure, disclosing hitherto unrecognized essential residues and domains in the homodimeric ABCG2 transporter. The elbow helix, the first intracellular loop (ICL1) and the nucleotide-binding domain (NBD) constitute pivotal elements of the architecture building the transmission interface that borders a central cavity which acts as a drug trap. The transmission interface is stabilized by salt-bridge interactions between the elbow helix and ICL1, as well as within ICL1, which is essential to control the conformational switch of ABCG2 to the outward-open drug-releasing conformation. Importantly, we propose that ICL1 operates like a molecular spring that holds the NBD dimer close to the membrane, thereby enabling efficient coupling of ATP hydrolysis during the catalytic cycle. These novel mechanistic data open new opportunities to therapeutically target ABCG2 in the context of related diseases. Nature Publishing Group UK 2017-10-23 /pmc/articles/PMC5653816/ /pubmed/29061978 http://dx.doi.org/10.1038/s41598-017-11794-w Text en © The Author(s) 2017 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Khunweeraphong, Narakorn Stockner, Thomas Kuchler, Karl The structure of the human ABC transporter ABCG2 reveals a novel mechanism for drug extrusion |
title | The structure of the human ABC transporter ABCG2 reveals a novel mechanism for drug extrusion |
title_full | The structure of the human ABC transporter ABCG2 reveals a novel mechanism for drug extrusion |
title_fullStr | The structure of the human ABC transporter ABCG2 reveals a novel mechanism for drug extrusion |
title_full_unstemmed | The structure of the human ABC transporter ABCG2 reveals a novel mechanism for drug extrusion |
title_short | The structure of the human ABC transporter ABCG2 reveals a novel mechanism for drug extrusion |
title_sort | structure of the human abc transporter abcg2 reveals a novel mechanism for drug extrusion |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653816/ https://www.ncbi.nlm.nih.gov/pubmed/29061978 http://dx.doi.org/10.1038/s41598-017-11794-w |
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