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Yorodumi- PDB-8hw2: Cryo-EM structure of beta-estradiol 17-(beta-D-glucuronide)-bound... -
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-Basic information
Entry | Database: PDB / ID: 8hw2 | ||||||
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Title | Cryo-EM structure of beta-estradiol 17-(beta-D-glucuronide)-bound human ABC transporter ABCC3 in nanodiscs | ||||||
Components | ATP-binding cassette sub-family C member 3 | ||||||
Keywords | MEMBRANE PROTEIN / ABC transporter / TRANSPORT PROTEIN / multidrug resistance protein | ||||||
Function / homology | Function and homology information glucuronoside transmembrane transporter activity / icosanoid transmembrane transporter activity / ABC-type bile acid transporter activity / leukotriene transport / ABC-type glutathione-S-conjugate transporter / ABC-type glutathione S-conjugate transporter activity / ATPase-coupled inorganic anion transmembrane transporter activity / xenobiotic transmembrane transport / ABC-type xenobiotic transporter / Paracetamol ADME ...glucuronoside transmembrane transporter activity / icosanoid transmembrane transporter activity / ABC-type bile acid transporter activity / leukotriene transport / ABC-type glutathione-S-conjugate transporter / ABC-type glutathione S-conjugate transporter activity / ATPase-coupled inorganic anion transmembrane transporter activity / xenobiotic transmembrane transport / ABC-type xenobiotic transporter / Paracetamol ADME / xenobiotic transport / bile acid and bile salt transport / NFE2L2 regulating MDR associated enzymes / ABC-type xenobiotic transporter activity / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / Aspirin ADME / xenobiotic transmembrane transporter activity / transport across blood-brain barrier / ATPase-coupled transmembrane transporter activity / ABC-type transporter activity / Recycling of bile acids and salts / xenobiotic metabolic process / basal plasma membrane / ABC-family proteins mediated transport / transmembrane transport / basolateral plasma membrane / ATP hydrolysis activity / ATP binding / membrane / plasma membrane Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.65 Å | ||||||
Authors | Wang, J. / Wang, F.F. / Chen, Y.X. / Zhou, C.Z. | ||||||
Funding support | China, 1items
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Citation | Journal: EMBO J / Year: 2023 Title: Placing steroid hormones within the human ABCC3 transporter reveals a compatible amphiphilic substrate-binding pocket. Authors: Jie Wang / Xu Li / Fang-Fang Wang / Meng-Ting Cheng / Yao-Xu Mao / Shu-Cheng Fang / Liang Wang / Cong-Zhao Zhou / Wen-Tao Hou / Yuxing Chen / Abstract: The human ABC transporter ABCC3 (also known as MRP3) transports a wide spectrum of substrates, including endogenous metabolites and exogenous drugs. Accordingly, it participates in multiple ...The human ABC transporter ABCC3 (also known as MRP3) transports a wide spectrum of substrates, including endogenous metabolites and exogenous drugs. Accordingly, it participates in multiple physiological processes and is involved in diverse human diseases such as intrahepatic cholestasis of pregnancy, which is caused by the intracellular accumulation of bile acids and estrogens. Here, we report three cryogenic electron microscopy structures of ABCC3: in the apo-form and in complexed forms bound to either the conjugated sex hormones β-estradiol 17-(β-D-glucuronide) and dehydroepiandrosterone sulfate. For both hormones, the steroid nuclei that superimpose against each other occupy the hydrophobic center of the transport cavity, whereas the two conjugation groups are separated and fixed by the hydrophilic patches in two transmembrane domains. Structural analysis combined with site-directed mutagenesis and ATPase activity assays revealed that ABCC3 possesses an amphiphilic substrate-binding pocket able to hold either conjugated hormone in an asymmetric pattern. These data build on consensus features of the substrate-binding pocket of MRPs and provide a structural platform for the rational design of inhibitors. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8hw2.cif.gz | 252.2 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8hw2.ent.gz | 199.7 KB | Display | PDB format |
PDBx/mmJSON format | 8hw2.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8hw2_validation.pdf.gz | 1.3 MB | Display | wwPDB validaton report |
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Full document | 8hw2_full_validation.pdf.gz | 1.3 MB | Display | |
Data in XML | 8hw2_validation.xml.gz | 50.1 KB | Display | |
Data in CIF | 8hw2_validation.cif.gz | 73.1 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/hw/8hw2 ftp://data.pdbj.org/pub/pdb/validation_reports/hw/8hw2 | HTTPS FTP |
-Related structure data
Related structure data | 35049MC 8hvhC 8hw4C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 169504.719 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: ABCC3, CMOAT2, MLP2, MRP3 / Cell line (production host): HEK 293F / Production host: Homo sapiens (human) References: UniProt: O15438, Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate, ABC-type xenobiotic transporter, ABC-type ...References: UniProt: O15438, Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate, ABC-type xenobiotic transporter, ABC-type glutathione-S-conjugate transporter | ||
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#2: Chemical | Has ligand of interest | Y | |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Human beta-estradiol 17-(beta-D-glucuronide)-bound ABC transporter ABCC3 in nanodiscs Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
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Molecular weight | Value: 169.4 kDa/nm / Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) / Cell: HEK 293F / Plasmid: pCAG |
Buffer solution | pH: 8 |
Specimen | Conc.: 1.85 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281 K |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1500 nm |
Image recording | Electron dose: 54 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.18.2_3874: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.65 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 177500 / Symmetry type: POINT | ||||||||||||||||||||||||
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