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Yorodumi- PDB-8y6i: P-glycoprotein in complex with UIC2 Fab and triple elacridar mole... -
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-Basic information
Entry | Database: PDB / ID: 8y6i | ||||||||||||
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Title | P-glycoprotein in complex with UIC2 Fab and triple elacridar molecules in nanodisc | ||||||||||||
Components |
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Keywords | MEMBRANE PROTEIN / ABC transporter / elacridar / P-glycoprotein | ||||||||||||
Function / homology | Function and homology information positive regulation of anion channel activity / ABC-type oligopeptide transporter activity / ceramide translocation / terpenoid transport / ceramide floppase activity / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / floppase activity / Abacavir transmembrane transport / external side of apical plasma membrane ...positive regulation of anion channel activity / ABC-type oligopeptide transporter activity / ceramide translocation / terpenoid transport / ceramide floppase activity / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / floppase activity / Abacavir transmembrane transport / external side of apical plasma membrane / regulation of response to osmotic stress / Atorvastatin ADME / phosphatidylethanolamine flippase activity / xenobiotic transport across blood-brain barrier / phosphatidylcholine floppase activity / xenobiotic detoxification by transmembrane export across the plasma membrane / export across plasma membrane / ABC-type xenobiotic transporter / transepithelial transport / P-type phospholipid transporter / ABC-type xenobiotic transporter activity / phospholipid translocation / Prednisone ADME / efflux transmembrane transporter activity / xenobiotic transmembrane transporter activity / transport across blood-brain barrier / transmembrane transporter activity / ATPase-coupled transmembrane transporter activity / xenobiotic metabolic process / bioluminescence / regulation of chloride transport / stem cell proliferation / ABC-family proteins mediated transport / transmembrane transport / G2/M transition of mitotic cell cycle / response to xenobiotic stimulus / apical plasma membrane / ubiquitin protein ligase binding / cell surface / ATP hydrolysis activity / extracellular exosome / ATP binding / membrane / plasma membrane / cytoplasm Similarity search - Function | ||||||||||||
Biological species | Homo sapiens (human) Mus musculus (house mouse) | ||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.54 Å | ||||||||||||
Authors | Hamaguchi-Suzuki, N. / Adachi, N. / Moriya, T. / Kawasaki, M. / Suzuki, K. / Anzai, N. / Senda, T. / Murata, T. | ||||||||||||
Funding support | Japan, 3items
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Citation | Journal: Biochem Biophys Res Commun / Year: 2024 Title: Cryo-EM structure of P-glycoprotein bound to triple elacridar inhibitor molecules. Authors: Norie Hamaguchi-Suzuki / Naruhiko Adachi / Toshio Moriya / Satoshi Yasuda / Masato Kawasaki / Kano Suzuki / Satoshi Ogasawara / Naohiko Anzai / Toshiya Senda / Takeshi Murata / Abstract: P-glycoprotein (P-gp) is an ATP-binding cassette transporter known for its roles in expelling xenobiotic compounds from cells and contributing to cellular drug resistance through multidrug efflux. ...P-glycoprotein (P-gp) is an ATP-binding cassette transporter known for its roles in expelling xenobiotic compounds from cells and contributing to cellular drug resistance through multidrug efflux. This mechanism is particularly problematic in cancer cells, where it diminishes the therapeutic efficacy of anticancer drugs. P-gp inhibitors, such as elacridar, have been developed to circumvent the decrease in drug efficacy due to P-gp efflux. An earlier study reported the cryo-EM structure of human P-gp-Fab (MRK-16) complex bound by two elacridar molecules, at a resolution of 3.6 Å. In this study, we have obtained a higher resolution (2.5 Å) structure of the P-gp- Fab (UIC2) complex bound by three elacridar molecules. This finding, which exposes a larger space for compound-binding sites than previously acknowledged, has significant implications for the development of more selective inhibitors and enhances our understanding of the compound recognition mechanism of P-gp. | ||||||||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8y6i.cif.gz | 262.6 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8y6i.ent.gz | 166 KB | Display | PDB format |
PDBx/mmJSON format | 8y6i.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/y6/8y6i ftp://data.pdbj.org/pub/pdb/validation_reports/y6/8y6i | HTTPS FTP |
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-Related structure data
Related structure data | 38987MC 8y6hC 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
-Protein , 1 types, 1 molecules A
#1: Protein | Mass: 170535.812 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: ABCB1, MDR1, PGY1, blFP-Y3 / Production host: Homo sapiens (human) References: UniProt: P08183, UniProt: A0A1S4NYF2, ABC-type xenobiotic transporter, P-type phospholipid transporter |
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-Antibody , 2 types, 2 molecules BC
#2: Antibody | Mass: 24321.039 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse) |
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#3: Antibody | Mass: 24381.281 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse) |
-Non-polymers , 3 types, 16 molecules
#4: Chemical | ChemComp-CLR / #5: Chemical | ChemComp-3PE / | #6: Chemical | |
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-Details
Has ligand of interest | Y |
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-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: Multidrug resistance proteinATP-binding cassette transporter Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3 |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 291 K |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: TFS KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 20000 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm |
Image recording | Electron dose: 48.8 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 4482 |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||
3D reconstruction | Resolution: 2.54 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 101021 / Symmetry type: POINT | ||||||||||||||||||||||||
Atomic model building | Space: RECIPROCAL | ||||||||||||||||||||||||
Atomic model building | PDB-ID: 6QEX Accession code: 6QEX / Source name: PDB / Type: experimental model | ||||||||||||||||||||||||
Refinement | Cross valid method: NONE Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||
Displacement parameters | Biso mean: 118.7 Å2 | ||||||||||||||||||||||||
Refine LS restraints |
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