5njg

Structure of an ABC transporter: part of the structure that could be built de novo

spinqualitylabelsall models 5njg, resolution 3.78Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5njg is a 6 chain structure with sequence from Human and Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: NAG Related: 5nj3 Gene: ABCG2, ABCP, BCRP, BCRP1, MXR (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [ABCG2_HUMAN] High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from the brain. Appears to play a major role in the multidrug resistance phenotype of several cancer cell lines. Implicated in the efflux of numerous drugs and xenobiotics: mitoxantrone, the photosensitizer pheophorbide, camptothecin, methotrexate, azidothymidine (AZT), and the anthracyclines daunorubicin and doxorubicin. Publication Abstract from PubMed ABCG2 is a constitutively expressed ATP-binding cassette (ABC) transporter that protects many tissues against xenobiotic molecules. Its activity affects the pharmacokinetics of commonly used drugs and limits the delivery of therapeutics into tumour cells, thus contributing to multidrug resistance. Here we present the structure of human ABCG2 determined by cryo-electron microscopy, providing the first high-resolution insight into a human multidrug transporter. We visualize ABCG2 in complex with two antigen-binding fragments of the human-specific, inhibitory antibody 5D3 that recognizes extracellular loops of the transporter. We observe two cholesterol molecules bound in the multidrug-binding pocket that is located in a central, hydrophobic, inward-facing translocation pathway between the transmembrane domains. Combined with functional in vitro analyses, our results suggest a multidrug recognition and transport mechanism of ABCG2, rationalize disease-causing single nucleotide polymorphisms and the allosteric inhibition by the 5D3 antibody, and provide the structural basis of cholesterol recognition by other G-subfamily ABC transporters. Structure of the human multidrug transporter ABCG2.,Taylor NMI, Manolaridis I, Jackson SM, Kowal J, Stahlberg H, Locher KP Nature. 2017 Jun 22;546(7659):504-509. doi: 10.1038/nature22345. Epub 2017 May, 29. PMID:28554189 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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