Structure of the human multidrug transporter ABCG2

Nicholas M. I. Taylor, Ioannis Manolaridis, Scott M. Jackson, Julia Kowal, Henning Stahlberg () and Kaspar P. Locher ()
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Nicholas M. I. Taylor: Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel
Ioannis Manolaridis: Institute of Molecular Biology and Biophysics, ETH Zürich
Scott M. Jackson: Institute of Molecular Biology and Biophysics, ETH Zürich
Julia Kowal: Institute of Molecular Biology and Biophysics, ETH Zürich
Henning Stahlberg: Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel
Kaspar P. Locher: Institute of Molecular Biology and Biophysics, ETH Zürich

Nature, 2017, vol. 546, issue 7659, 504-509

Abstract: Abstract ABCG2 is a constitutively expressed ATP-binding cassette (ABC) transporter that protects many tissues against xenobiotic molecules. Its activity affects the pharmacokinetics of commonly used drugs and limits the delivery of therapeutics into tumour cells, thus contributing to multidrug resistance. Here we present the structure of human ABCG2 determined by cryo-electron microscopy, providing the first high-resolution insight into a human multidrug transporter. We visualize ABCG2 in complex with two antigen-binding fragments of the human-specific, inhibitory antibody 5D3 that recognizes extracellular loops of the transporter. We observe two cholesterol molecules bound in the multidrug-binding pocket that is located in a central, hydrophobic, inward-facing translocation pathway between the transmembrane domains. Combined with functional in vitro analyses, our results suggest a multidrug recognition and transport mechanism of ABCG2, rationalize disease-causing single nucleotide polymorphisms and the allosteric inhibition by the 5D3 antibody, and provide the structural basis of cholesterol recognition by other G-subfamily ABC transporters.

Date: 2017
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DOI: 10.1038/nature22345

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