Inward- and outward-facing X-ray crystal structures of homodimeric P-glycoprotein CmABCB1

Atsushi Kodan, Tomohiro Yamaguchi, Toru Nakatsu, Keita Matsuoka, Yasuhisa Kimura, Kazumitsu Ueda and Hiroaki Kato ()
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Atsushi Kodan: Kyoto University
Tomohiro Yamaguchi: Kyoto University
Toru Nakatsu: Kyoto University
Keita Matsuoka: Kyoto University
Yasuhisa Kimura: Kyoto University
Kazumitsu Ueda: Kyoto University
Hiroaki Kato: Kyoto University

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract P-glycoprotein extrudes a large variety of xenobiotics from the cell, thereby protecting tissues from their toxic effects. The machinery underlying unidirectional multidrug pumping remains unknown, largely due to the lack of high-resolution structural information regarding the alternate conformational states of the molecule. Here we report a pair of structures of homodimeric P-glycoprotein: an outward-facing conformational state with bound nucleotide and an inward-facing apo state, at resolutions of 1.9 Å and 3.0 Å, respectively. Features that can be clearly visualized at this high resolution include ATP binding with octahedral coordination of Mg2+; an inner chamber that significantly changes in volume with the aid of tight connections among transmembrane helices (TM) 1, 3, and 6; a glutamate−arginine interaction that stabilizes the outward-facing conformation; and extensive interactions between TM1 and TM3, a property that distinguishes multidrug transporters from floppases. These structural elements are proposed to participate in the mechanism of the transporter.

Date: 2019
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DOI: 10.1038/s41467-018-08007-x

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