The structure of the human ABC transporter ABCG2 reveals a novel mechanism for drug extrusion

Abstract 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...

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Autores principales:	Narakorn Khunweeraphong, Thomas Stockner, Karl Kuchler
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c2c9f38203e64d76aa5b081be233b11c
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spelling	oai:doaj.org-article:c2c9f38203e64d76aa5b081be233b11c2021-12-02T15:05:40ZThe structure of the human ABC transporter ABCG2 reveals a novel mechanism for drug extrusion10.1038/s41598-017-11794-w2045-2322https://doaj.org/article/c2c9f38203e64d76aa5b081be233b11c2017-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-11794-whttps://doaj.org/toc/2045-2322Abstract 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.Narakorn KhunweeraphongThomas StocknerKarl KuchlerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Narakorn Khunweeraphong Thomas Stockner Karl Kuchler The structure of the human ABC transporter ABCG2 reveals a novel mechanism for drug extrusion
description	Abstract 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	article
author	Narakorn Khunweeraphong Thomas Stockner Karl Kuchler
author_facet	Narakorn Khunweeraphong Thomas Stockner Karl Kuchler
author_sort	Narakorn Khunweeraphong
title	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_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_sort	structure of the human abc transporter abcg2 reveals a novel mechanism for drug extrusion
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/c2c9f38203e64d76aa5b081be233b11c
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_version_	1718388792111398912

The structure of the human ABC transporter ABCG2 reveals a novel mechanism for drug extrusion

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