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DOI	10.1073/pnas.2106702118
	Structures of ABCB4 provide insight into phosphatidylcholine translocation
	Nosol K.; Bang-Sørensen R.; Irobalieva R.N.; Erramilli S.K.; Stieger B.; Kossiakoff A.A.; Locher K.P.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:33
英文摘要	ABCB4 is expressed in hepatocytes and translocates phosphatidylcholine into bile canaliculi. The mechanism of specific lipid recruitment from the canalicular membrane, which is essential to mitigate the cytotoxicity of bile salts, is poorly understood. We present cryogenic electron microscopy structures of human ABCB4 in three distinct functional conformations. An apo-inward structure reveals how phospholipid can be recruited from the inner leaflet of the membrane without flipping its orientation. An occluded structure reveals a single phospholipid molecule in a central cavity. Its choline moiety is stabilized by cation-π interactions with an essential tryptophan residue, rationalizing the specificity of ABCB4 for phosphatidylcholine. In an inhibitor-bound structure, a posaconazole molecule blocks phospholipids from reaching the central cavity. Using a proteoliposomebased translocation assay with fluorescently labeled phosphatidylcholine analogs, we recapitulated the substrate specificity of ABCB4 in vitro and confirmed the role of the key tryptophan residue. Our results provide a structural basis for understanding an essential translocation step in the generation of bile and its sensitivity to azole drugs. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	ABC transporter; Cryo-EM; Hepatocyte; Membrane transport; Phosphatidylcholine
语种	英语
scopus关键词	ABC transporter; bile salt; cation; choline; multidrug resistance protein 3; phosphatidylcholine; posaconazole; proteoliposome; tryptophan; epitope; immunoglobulin F(ab) fragment; multidrug resistance protein 3; phosphatidylcholine; Article; controlled study; cryoelectron microscopy; enzyme specificity; fluorescence; in vitro study; inner membrane; liver cell; liver function; membrane transport; nonhuman; protein conformation; protein expression; protein lipid interaction; cell surface display; chemistry; gene expression regulation; genetic variation; genetics; HEK293 cell line; human; metabolism; molecular model; protein conformation; transport at the cellular level; ATP Binding Cassette Transporter, Subfamily B; Biological Transport; Cell Surface Display Techniques; Cryoelectron Microscopy; Epitopes; Gene Expression Regulation; Genetic Variation; HEK293 Cells; Humans; Immunoglobulin Fab Fragments; Models, Molecular; Phosphatidylcholines; Protein Conformation
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251061
作者单位	Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, 8093, Switzerland; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, United States; Department of Clinical Pharmacology and Toxicology, University Hospital Zürich, University of Zürich, Zürich, 8091, Switzerland
推荐引用方式 GB/T 7714	Nosol K.,Bang-Sørensen R.,Irobalieva R.N.,et al. Structures of ABCB4 provide insight into phosphatidylcholine translocation[J],2021,118(33).
APA	Nosol K..,Bang-Sørensen R..,Irobalieva R.N..,Erramilli S.K..,Stieger B..,...&Locher K.P..(2021).Structures of ABCB4 provide insight into phosphatidylcholine translocation.Proceedings of the National Academy of Sciences of the United States of America,118(33).
MLA	Nosol K.,et al."Structures of ABCB4 provide insight into phosphatidylcholine translocation".Proceedings of the National Academy of Sciences of the United States of America 118.33(2021).