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

Narakorn Khunweeraphong, Daniel Szöllősi, Thomas Stockner and Karl Kuchler ()
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Narakorn Khunweeraphong: Medical University of Vienna
Daniel Szöllősi: Medical University of Vienna
Thomas Stockner: Medical University of Vienna
Karl Kuchler: Medical University of Vienna

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13302-2

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