|Entry||Database: PDB / ID: 6qee|
|Title||Nanodisc reconstituted Human-mouse chimeric ABCB1 (ABCB1HM)-EQ mutant in complex with UIC2 Fab and Zosuquidar.|
|Keywords||MEMBRANE PROTEIN / ABCB1 / p-glycoprotein / p-gp / multidrug transporter / ABC transporter / zosuquidar / membrane transporter|
|Specimen source||Homo sapiens (human)|
Mus musculus (house mouse)
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / 3.9 Å resolution|
|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.
SummaryFull reportAbout validation report
|Date||Deposition: Jan 7, 2019 / Release: Feb 27, 2019|
|Structure viewer||Molecule: |
Downloads & links
B: UIC2 Antigen Binding Fragment Light chain
C: UIC2 Antigen Binding Fragment Heavy Chain
-Protein/peptide , 1 types, 1 molecules A
|#1: Protein/peptide|| |
Mass: 143627.828 Da / Num. of mol.: 1 / Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
-UIC2 Antigen Binding Fragment ... , 2 types, 2 molecules B
|#2: Protein/peptide|| |
Mass: 24321.039 Da / Num. of mol.: 1 / Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse)
|#3: Protein/peptide|| |
Mass: 24381.281 Da / Num. of mol.: 1 / Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse)
-Non-polymers , 4 types, 13 molecules
|#4: Chemical||#5: Chemical||#6: Chemical|
|#7: Chemical|| ChemComp-3PE / |
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / Reconstruction method: single particle reconstruction|
|Molecular weight||Value: 0.2 MDa / Experimental value: YES|
|Buffer solution||pH: 7.5|
|Specimen||Conc.: 0.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Specimen support||Grid material: COPPER / Grid type: Quantifoil R1.2/1.3|
|Vitrification||Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE-PROPANE / Humidity: 100 % / Chamber temperature: 277 kelvins|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Microscope 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: 2.1 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)|
|Software||Name: PHENIX / Version: 1.14_3260: / Classification: refinement|
|CTF correction||Type: PHASE FLIPPING AND AMPLITUDE CORRECTION|
|Symmetry||Point symmetry: C1|
|3D reconstruction||Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number of particles: 291197 / Symmetry type: POINT|
|Refine||Stereochemistry target values: CDL v1.2|
|Refine LS restraints|
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