ArticleProceedings of the National Academy of Sciences of the United States of America2021
Structures of ABCB4 provide insight into phosphatidylcholine translocation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 42 citations in OpenAlex.
- Decoding the Cellular Response to Methylthioadenosine Uncovers Novel Targets for Chronic Liver Disease.Cells · 2026Article
- Molecular characterisation of the trafficking rescue of defective ABCB4 variants by roscovitine analogues.Scientific reports · 2026Article
- Conformational ensembles of the magnesium channel CorA reveal structural basis for channel gating.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Metabolite-mediated crosstalk: unraveling the interactions between gut microbiota and host in fatty liver hemorrhagic syndrome of laying hens.Journal of animal science and biotechnology · 2026Review
- Functional inactivation of MDR3 caused by a homozygousFrontiers in genetics · 2026Article
- ABCB4 disease-causing variants S242R, S346I, T437I and T1077M significantly impair its function and display differential sensitivity to potentiators.Scientific reports · 2025Article
- Association between ABCB4 variants and intrahepatic cholestasis of pregnancy.Scientific reports · 2025Article
- Membrane-dependent dynamics and dual translocation mechanisms of ABCB4: Insights from molecular dynamics simulations.Computational and structural biotechnology journal · 2025Article
- Mechanistic insights into P-glycoprotein ligand transport and inhibition revealed by enhanced molecular dynamics simulations.Computational and structural biotechnology journal · 2024Article
- ATP-Binding Cassette and Solute Carrier Transporters: Understanding Their Mechanisms and Drug Modulation Through Structural and Modeling Approaches.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Identification of new correctors for traffic-defective ABCB4 variants by a high-content screening approach.Communications biology · 2024Article
- Structural basis of bile salt extrusion and small-molecule inhibition in human BSEP.Nature communications · 2023Article
- PGP-14 establishes a polar lipid permeability barrier within the C. elegans pharyngeal cuticle.PLoS genetics · 2023Article
- Reconstitution of ATP-dependent lipid transporters: gaining insight into molecular characteristics, regulation, and mechanisms.Bioscience reports · 2023Review
- Residues from Homologous Transmembrane Helices 4 and 10 Are Critical for P-Glycoprotein (ABCB1)-Mediated Drug Transport.Cancers · 2023Article
- Rare variant contribution to cholestatic liver disease in a South Asian population in the United Kingdom.Scientific reports · 2023Article
- Effects of Biliary Phospholipids on Cholesterol Crystallization and Growth in Gallstone Formation.Advances in therapy · 2023Review
- Article
- Structural and functional investigation of ABC transporter STE6-2p fromProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Membranes under the Magnetic Lens: A Dive into the Diverse World of Membrane Protein Structures Using Cryo-EM.Chemical reviews · 2022Review
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
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 proteoliposome-based 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.