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- EMDB-4541: Nanodisc reconstituted human ABCB1 in complex with UIC2 fab and taxol -

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Basic information

Entry
Database: EMDB / ID: 4541
TitleNanodisc reconstituted human ABCB1 in complex with UIC2 fab and taxol
Map datapostprocessed map of human ABCB1 in complex with UIC2 fab and taxol after partial nanodisc signal subtraction.
SampleNanodisc reconstituted ABCB1HM (human mouse chimeric ABCB1) EQ mutant in complex with UIC2 Fab and zosuquidar
  • nanodisc reconstituted human ABCB1 in complex with UIC2 Fab and taxol
  • UIC2 Fab
SourceHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / 3.7 Å resolution
AuthorsAlam A / Locher KP
CitationJournal: 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.
DateDeposition: Jan 8, 2019 / Header (metadata) release: Feb 27, 2019 / Map release: Feb 27, 2019 / Last update: Feb 27, 2019

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.007
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by height
  • Surface level: 0.007
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

Fileemd_4541.map.gz (map file in CCP4 format, 256001 KB)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
400 pix
0.84 Å/pix.
= 336. Å
400 pix
0.84 Å/pix.
= 336. Å
400 pix
0.84 Å/pix.
= 336. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.84 Å
Density
Contour Level:0.005 (by author), 0.007 (movie #1):
Minimum - Maximum-0.028097168 - 0.053256687
Average (Standard dev.)-0.000049445738 (0.0009119551)
Details

EMDB XML:

Space Group Number1
Map Geometry
Axis orderXYZ
Dimensions400400400
Origin0.00.00.0
Limit399.0399.0399.0
Spacing400400400
CellA=B=C: 336.0 Å
α=β=γ: 90.0 deg.

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.840.840.84
M x/y/z400400400
origin x/y/z0.0000.0000.000
length x/y/z336.000336.000336.000
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ364364364
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS400400400
D min/max/mean-0.0280.053-0.000

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Supplemental data

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Sample components

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Entire Nanodisc reconstituted ABCB1HM (human mouse chimeric ABCB1) EQ mu...

EntireName: Nanodisc reconstituted ABCB1HM (human mouse chimeric ABCB1) EQ mutant in complex with UIC2 Fab and zosuquidar
Number of components: 3

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Component #1: protein, Nanodisc reconstituted ABCB1HM (human mouse chimeric ABC...

ProteinName: Nanodisc reconstituted ABCB1HM (human mouse chimeric ABCB1) EQ mutant in complex with UIC2 Fab and zosuquidar
Recombinant expression: No
MassExperimental: 200 kDa

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Component #2: protein, nanodisc reconstituted human ABCB1 in complex with UIC2 ...

ProteinName: nanodisc reconstituted human ABCB1 in complex with UIC2 Fab and taxol
Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #3: protein, UIC2 Fab

ProteinName: UIC2 Fab / Recombinant expression: No
SourceSpecies: Mus musculus (house mouse)

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Experimental details

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Sample preparation

SpecimenSpecimen state: particle / Method: cryo EM
Sample solutionSpecimen conc.: 0.2 mg/ml / pH: 7.5
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: OTHER / Temperature: 277 K / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 2.1 e/Å2 / Illumination mode: FLOOD BEAM
LensImaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 SUMMIT (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Applied symmetry: C1 (asymmetric) / Number of projections: 240262
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF
FSC plot
(resolution estimation)

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