+Open data
-Basic information
Entry | Database: PDB / ID: 6gdi | ||||||
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Title | Structure of P-glycoprotein(ABCB1) in the post-hydrolytic state | ||||||
Components | Multidrug resistance protein 1AMultiple drug resistance | ||||||
Keywords | MEMBRANE PROTEIN / P-glycoprotein / ABCB1 / ATP-binding cassette / transporter / protein structure | ||||||
Function / homology | Function and homology information hormone transport / cellular response to borneol / response to codeine / response to cyclosporin A / Atorvastatin ADME / cellular response to mycotoxin / daunorubicin transport / positive regulation of response to drug / response to quercetin / cellular response to external biotic stimulus ...hormone transport / cellular response to borneol / response to codeine / response to cyclosporin A / Atorvastatin ADME / cellular response to mycotoxin / daunorubicin transport / positive regulation of response to drug / response to quercetin / cellular response to external biotic stimulus / regulation of intestinal absorption / response to antineoplastic agent / Prednisone ADME / positive regulation of establishment of Sertoli cell barrier / ceramide translocation / terpenoid transport / ceramide floppase activity / response to glycoside / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / floppase activity / establishment of blood-retinal barrier / protein localization to bicellular tight junction / regulation of response to osmotic stress / cellular response to L-glutamate / ABC-family proteins mediated transport / establishment of blood-brain barrier / response to thyroxine / phosphatidylcholine floppase activity / phosphatidylethanolamine flippase activity / xenobiotic transport across blood-brain barrier / xenobiotic detoxification by transmembrane export across the plasma membrane / export across plasma membrane / response to vitamin D / ABC-type xenobiotic transporter / intercellular canaliculus / transepithelial transport / P-type phospholipid transporter / ABC-type xenobiotic transporter activity / response to vitamin A / response to glucagon / intestinal absorption / phospholipid translocation / cellular response to antibiotic / maintenance of blood-brain barrier / cellular hyperosmotic salinity response / cellular response to alkaloid / xenobiotic transmembrane transporter activity / efflux transmembrane transporter activity / transmembrane transporter activity / ATPase-coupled transmembrane transporter activity / response to cadmium ion / lactation / cellular response to dexamethasone stimulus / placenta development / regulation of chloride transport / stem cell proliferation / cellular response to estradiol stimulus / brush border membrane / circadian rhythm / G2/M transition of mitotic cell cycle / cellular response to tumor necrosis factor / cellular response to lipopolysaccharide / response to hypoxia / response to xenobiotic stimulus / apical plasma membrane / ubiquitin protein ligase binding / cell surface / ATP hydrolysis activity / ATP binding / membrane / plasma membrane / cytoplasm Similarity search - Function | ||||||
Biological species | Mus musculus (house mouse) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 7.9 Å | ||||||
Authors | Ford, R.C. / Thonghin, N. / Collins, R.F. / Barbieri, A. / Shafi, T. / Siebert, A. | ||||||
Citation | Journal: BMC Struct Biol / Year: 2018 Title: Novel features in the structure of P-glycoprotein (ABCB1) in the post-hydrolytic state as determined at 7.9 Å resolution. Authors: Nopnithi Thonghin / Richard F Collins / Alessandro Barbieri / Talha Shafi / Alistair Siebert / Robert C Ford / Abstract: BACKGROUND: P-glycoprotein (ABCB1) is an ATP-binding cassette transporter that plays an important role in the clearance of drugs and xenobiotics and is associated with multi-drug resistance in cancer. ...BACKGROUND: P-glycoprotein (ABCB1) is an ATP-binding cassette transporter that plays an important role in the clearance of drugs and xenobiotics and is associated with multi-drug resistance in cancer. Although several P-glycoprotein structures are available, these are either at low resolution, or represent mutated and/or quiescent states of the protein. RESULTS: In the post-hydrolytic state the structure of the wild-type protein has been resolved at about 8 Å resolution. The cytosolic nucleotide-binding domains (NBDs) are separated but ADP ...RESULTS: In the post-hydrolytic state the structure of the wild-type protein has been resolved at about 8 Å resolution. The cytosolic nucleotide-binding domains (NBDs) are separated but ADP remains bound, especially at the first NBD. Gaps in the transmembrane domains (TMDs) that connect to an inner hydrophilic cavity are filled by density emerging from the annular detergent micelle. The NBD-TMD linker is partly resolved, being located between the NBDs and close to the Signature regions involved in cooperative NBD dimerization. This, and the gap-filling detergent suggest steric impediment to NBD dimerization in the post-hydrolytic state. Two central regions of density lie in two predicted drug-binding sites, implying that the protein may adventitiously bind hydrophobic substances even in the post-hydrolytic state. The previously unresolved N-terminal extension was observed, and the data suggests these 30 residues interact with the headgroup region of the lipid bilayer. CONCLUSION: The structural data imply that (i) a low basal ATPase activity is ensured by steric blockers of NBD dimerization and (ii) allocrite access to the central cavity may be structurally linked ...CONCLUSION: The structural data imply that (i) a low basal ATPase activity is ensured by steric blockers of NBD dimerization and (ii) allocrite access to the central cavity may be structurally linked to NBD dimerization, giving insights into the mechanism of drug-stimulation of P-glycoprotein activity. | ||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 6gdi.cif.gz | 207.2 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6gdi.ent.gz | 163.4 KB | Display | PDB format |
PDBx/mmJSON format | 6gdi.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/gd/6gdi ftp://data.pdbj.org/pub/pdb/validation_reports/gd/6gdi | HTTPS FTP |
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-Related structure data
Related structure data | 4391MC 6q81C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 141877.875 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse) / Gene: Abcb1a, Abcb4, Mdr1a, Mdr3, Pgy-3, Pgy3 / Production host: Komagataella pastoris (fungus) / References: UniProt: P21447, xenobiotic-transporting ATPase |
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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: mouse P-glycoprotein / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT |
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Molecular weight | Experimental value: NO |
Source (natural) | Organism: Mus musculus (house mouse) |
Source (recombinant) | Organism: Komagataella pastoris (fungus) |
Buffer solution | pH: 8 |
Specimen | Conc.: 1.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: GOLD / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3 |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 295 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: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy |
Image recording | Electron dose: 70 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||
3D reconstruction | Resolution: 7.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 135357 / Num. of class averages: 18 / Symmetry type: POINT | ||||||||||||||||
Atomic model building | Protocol: FLEXIBLE FIT | ||||||||||||||||
Atomic model building | PDB-ID: 4KSB Pdb chain-ID: a / Pdb chain residue range: 33-1271 |