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Yorodumi- PDB-6qex: Nanodisc reconstituted human ABCB1 in complex with UIC2 fab and taxol -
+Open data
-Basic information
Entry | Database: PDB / ID: 6qex | |||||||||
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Title | Nanodisc reconstituted human ABCB1 in complex with UIC2 fab and taxol | |||||||||
Components |
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Keywords | MEMBRANE PROTEIN / ABCB1 / p-glycoprotein / p-gp / multidrug exporter / ABC transporter | |||||||||
Function / homology | Function and homology information positive regulation of anion channel activity / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / external side of apical plasma membrane / terpenoid transport / ceramide floppase activity / regulation of response to osmotic stress / ceramide translocation / floppase activity / Abacavir transmembrane transport ...positive regulation of anion channel activity / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / external side of apical plasma membrane / terpenoid transport / ceramide floppase activity / regulation of response to osmotic stress / ceramide translocation / floppase activity / Abacavir transmembrane transport / Atorvastatin ADME / phosphatidylethanolamine flippase activity / phosphatidylcholine floppase activity / xenobiotic transport across blood-brain barrier / transepithelial transport / export across plasma membrane / ABC-type xenobiotic transporter / xenobiotic detoxification by transmembrane export across the plasma membrane / 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 / ATPase-coupled transmembrane transporter activity / transmembrane transporter activity / xenobiotic metabolic process / 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: 3.6 Å | |||||||||
Authors | Alam, A. / Locher, K.P. | |||||||||
Funding support | Switzerland, 2items
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Citation | Journal: Science / Year: 2019 Title: Structural insight into substrate and inhibitor discrimination by human P-glycoprotein. Authors: Amer Alam / Julia Kowal / Eugenia Broude / Igor Roninson / Kaspar P Locher / Abstract: ABCB1, also known as P-glycoprotein, actively extrudes xenobiotic compounds across the plasma membrane of diverse cells, which contributes to cellular drug resistance and interferes with therapeutic ...ABCB1, also known as P-glycoprotein, actively extrudes xenobiotic compounds across the plasma membrane of diverse cells, which contributes to cellular drug resistance and interferes with therapeutic drug delivery. We determined the 3.5-angstrom cryo-electron microscopy structure of substrate-bound human ABCB1 reconstituted in lipidic nanodiscs, revealing a single molecule of the chemotherapeutic compound paclitaxel (Taxol) bound in a central, occluded pocket. A second structure of inhibited, human-mouse chimeric ABCB1 revealed two molecules of zosuquidar occupying the same drug-binding pocket. Minor structural differences between substrate- and inhibitor-bound ABCB1 sites are amplified toward the nucleotide-binding domains (NBDs), revealing how the plasticity of the drug-binding site controls the dynamics of the adenosine triphosphate-hydrolyzing NBDs. Ordered cholesterol and phospholipid molecules suggest how the membrane modulates the conformational changes associated with drug binding and transport. | |||||||||
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 | 6qex.cif.gz | 303.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6qex.ent.gz | 253.1 KB | Display | PDB format |
PDBx/mmJSON format | 6qex.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6qex_validation.pdf.gz | 2 MB | Display | wwPDB validaton report |
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Full document | 6qex_full_validation.pdf.gz | 2 MB | Display | |
Data in XML | 6qex_validation.xml.gz | 61.2 KB | Display | |
Data in CIF | 6qex_validation.cif.gz | 91.1 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/qe/6qex ftp://data.pdbj.org/pub/pdb/validation_reports/qe/6qex | HTTPS FTP |
-Related structure data
Related structure data | 4539MC 4536C 4540C 4541C 6qeeC C: citing same article (ref.) M: map data used to model this data |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Antibody , 2 types, 2 molecules BC
#2: Antibody | Mass: 24321.039 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) |
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#3: Antibody | Mass: 24381.281 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) |
-Protein / Sugars , 2 types, 4 molecules A
#1: Protein | Mass: 141628.781 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: ABCB1, MDR1, PGY1 / Production host: Homo sapiens (human) References: UniProt: P08183, ABC-type xenobiotic transporter |
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#4: Sugar |
-Non-polymers , 3 types, 19 molecules
#5: Chemical | ChemComp-CLR / #6: Chemical | ChemComp-TA1 / | #7: Chemical | |
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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 |
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Molecular weight | Value: 0.2 MDa / Experimental value: YES | ||||||||||||||||||||||||
Source (natural) |
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Source (recombinant) | Organism: Homo sapiens (human) | ||||||||||||||||||||||||
Buffer solution | pH: 7.5 | ||||||||||||||||||||||||
Specimen | Conc.: 0.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE-PROPANE / Humidity: 100 % / Chamber temperature: 277 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 FIELD |
Image recording | Electron dose: 2.1 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.14_3260: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 262191 / Symmetry type: POINT | ||||||||||||||||||||||||
Refinement | Stereochemistry target values: CDL v1.2 | ||||||||||||||||||||||||
Refine LS restraints |
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