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The ABCG2 multidrug transporter is a pump gated by a valve and an extracellular lid

Author

Listed:
  • Narakorn Khunweeraphong

    (Medical University of Vienna)

  • Daniel Szöllősi

    (Medical University of Vienna)

  • Thomas Stockner

    (Medical University of Vienna)

  • Karl Kuchler

    (Medical University of Vienna)

Abstract

The human ATP-binding cassette transporter ABCG2 is a key to anticancer resistance and physiological detoxification. However, the molecular mechanism of substrate transport remains enigmatic. A hydrophobic di-leucine motif in the ABCG2 core separates a large intracellular cavity from a smaller upper cavity. We show that the di-leucine motif acts as a valve that controls drug extrusion. Moreover, the extracellular structure engages the re-entry helix and all extracellular loops to form a roof architecture on top of the upper cavity. Disulfide bridges and a salt bridge limit roof flexibility, but provide a lid-like function to control drug release. We propose that drug translocation from the central to the upper cavities through the valve is driven by a squeezing motion, suggesting that ABCG2 operates similar to a peristaltic pump. Finally, the roof contains essential residues, offering therapeutic options to block ABCG2 by either targeting the valve or essential residues in the roof.

Suggested Citation

  • Narakorn Khunweeraphong & Daniel Szöllősi & Thomas Stockner & Karl Kuchler, 2019. "The ABCG2 multidrug transporter is a pump gated by a valve and an extracellular lid," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13302-2
    DOI: 10.1038/s41467-019-13302-2
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    Cited by:

    1. Tomoka Gose & Heather M. Aitken & Yao Wang & John Lynch & Evadnie Rampersaud & Yu Fukuda & Medb Wills & Stefanie A. Baril & Robert C. Ford & Anang Shelat & Megan L. O’Mara & John D. Schuetz, 2023. "The net electrostatic potential and hydration of ABCG2 affect substrate transport," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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