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Structure of the human multidrug transporter ABCG2

Author

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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)

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.

Suggested Citation

  • Nicholas M. I. Taylor & Ioannis Manolaridis & Scott M. Jackson & Julia Kowal & Henning Stahlberg & Kaspar P. Locher, 2017. "Structure of the human multidrug transporter ABCG2," Nature, Nature, vol. 546(7659), pages 504-509, June.
  • Handle: RePEc:nat:nature:v:546:y:2017:i:7659:d:10.1038_nature22345
    DOI: 10.1038/nature22345
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    Cited by:

    1. Noreddine Benkerroum & Amir Ismail, 2022. "Human Breast Milk Contamination with Aflatoxins, Impact on Children’s Health, and Possible Control Means: A Review," IJERPH, MDPI, vol. 19(24), pages 1-34, December.

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