|Entry||Database: EMDB / ID: 4541|
|Title||Nanodisc reconstituted human ABCB1 in complex with UIC2 fab and taxol|
|Map data||postprocessed map of human ABCB1 in complex with UIC2 fab and taxol after partial nanodisc signal subtraction.|
|Sample||Nanodisc reconstituted ABCB1HM (human mouse chimeric ABCB1) EQ mutant in complex with UIC2 Fab and zosuquidar|
|Source||Homo sapiens (human) / Mus musculus (house mouse)|
|Method||single particle reconstruction / cryo EM / 3.7 Å resolution|
|Authors||Alam A / Locher KP|
|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.
|Date||Deposition: Jan 8, 2019 / Header (metadata) release: Feb 27, 2019 / Map release: Feb 27, 2019 / Last update: Feb 27, 2019|
|Structure viewer||EM map: |
Downloads & links
|File||emd_4541.map.gz (map file in CCP4 format, 256001 KB)|
|Projections & slices|
Images are generated by Spider.
|Voxel size||X=Y=Z: 0.84 Å|
CCP4 map header:
-Entire Nanodisc reconstituted ABCB1HM (human mouse chimeric ABCB1) EQ mu...
|Entire||Name: Nanodisc reconstituted ABCB1HM (human mouse chimeric ABCB1) EQ mutant in complex with UIC2 Fab and zosuquidar|
Number of components: 3
-Component #1: protein, Nanodisc reconstituted ABCB1HM (human mouse chimeric ABC...
|Protein||Name: Nanodisc reconstituted ABCB1HM (human mouse chimeric ABCB1) EQ mutant in complex with UIC2 Fab and zosuquidar|
Recombinant expression: No
|Mass||Experimental: 200 kDa|
-Component #2: protein, nanodisc reconstituted human ABCB1 in complex with UIC2 ...
|Protein||Name: nanodisc reconstituted human ABCB1 in complex with UIC2 Fab and taxol|
Recombinant expression: No
|Source||Species: Homo sapiens (human)|
|Source (engineered)||Expression System: Homo sapiens (human)|
-Component #3: protein, UIC2 Fab
|Protein||Name: UIC2 Fab / Recombinant expression: No|
|Source||Species: Mus musculus (house mouse)|
|Specimen||Specimen state: particle / Method: cryo EM|
|Sample solution||Specimen conc.: 0.2 mg/ml / pH: 7.5|
|Vitrification||Instrument: FEI VITROBOT MARK IV / Cryogen name: OTHER / Temperature: 277 K / Humidity: 100 %|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Imaging||Microscope: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 2.1 e/Å2 / Illumination mode: FLOOD BEAM|
|Lens||Imaging mode: BRIGHT FIELD|
|Specimen Holder||Model: OTHER|
|Camera||Detector: GATAN K2 SUMMIT (4k x 4k)|
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