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


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.

SUBMITTER: Kodan A 

PROVIDER: S-EPMC6325147 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Kodan Atsushi A   Yamaguchi Tomohiro T   Nakatsu Toru T   Matsuoka Keita K   Kimura Yasuhisa Y   Ueda Kazumitsu K   Kato Hiroaki H  

Nature communications 20190108 1


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 resolution  ...[more]

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