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- Journal Article
Cryo-EM structure of human transporter ABCB4 that extrudes phosphatidylcholine into the bile canaliculi suggests an 'alternating access' mechanism of lipid extrusion, distinct from the 'credit card swipe' model of other lipid transporters. ABCB4 is an ATP-binding cassette transporter that extrudes phosphatidylcholine into the bile canaliculi of the liver. Its dysfunction or inhibition by drugs can cause severe, chronic liver disease or drug-induced liver injury. We determined the cryo-EM structure of nanodisc-reconstituted human ABCB4 trapped in an ATP-bound state at a resolution of 3.2 angstrom. The nucleotide binding domains form a closed conformation containing two bound ATP molecules, but only one of the ATPase sites contains bound Mg2+. The transmembrane domains adopt a collapsed conformation at the level of the lipid bilayer, but we observed a large, hydrophilic and fully occluded cavity at the level of the cytoplasmic membrane boundary, with no ligand bound. This indicates a state following substrate release but prior to ATP hydrolysis. Our results rationalize disease-causing mutations in human ABCB4 and suggest an 'alternating access' mechanism of lipid extrusion, distinct from the 'credit card swipe' model of other lipid transporters. Show more
Journal / seriesNature Structural & Molecular Biology
Pages / Article No.
PublisherNATURE PUBLISHING GROUP
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