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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: EMD-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.
Sample
  • Complex: Nanodisc reconstituted ABCB1HM (human mouse chimeric ABCB1) EQ mutant in complex with UIC2 Fab and zosuquidar
    • Complex: nanodisc reconstituted human ABCB1 in complex with UIC2 Fab and taxol
    • Complex: UIC2 Fab
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
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.
History
DepositionJan 8, 2019-
Header (metadata) releaseFeb 27, 2019-
Map releaseFeb 27, 2019-
UpdateFeb 27, 2019-
Current statusFeb 27, 2019Processing site: PDBe / Status: Released

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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

emd_4541.png

Downloads & links

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Map

FileDownload / File: emd_4541.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationpostprocessed map of human ABCB1 in complex with UIC2 fab and taxol after partial nanodisc signal subtraction.
Voxel sizeX=Y=Z: 0.84 Å
Density
Contour LevelBy AUTHOR: 0.005 / Movie #1: 0.007
Minimum - Maximum-0.028097168 - 0.053256687
Average (Standard dev.)-0.000049445738 (±0.0009119551)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 336.0 Å
α=β=γ: 90.0 °

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
Components
  • Complex: Nanodisc reconstituted ABCB1HM (human mouse chimeric ABCB1) EQ mutant in complex with UIC2 Fab and zosuquidar
    • Complex: nanodisc reconstituted human ABCB1 in complex with UIC2 Fab and taxol
    • Complex: UIC2 Fab

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Supramolecule #1: Nanodisc reconstituted ABCB1HM (human mouse chimeric ABCB1) EQ mu...

SupramoleculeName: Nanodisc reconstituted ABCB1HM (human mouse chimeric ABCB1) EQ mutant in complex with UIC2 Fab and zosuquidar
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Molecular weightExperimental: 200 KDa

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Supramolecule #2: nanodisc reconstituted human ABCB1 in complex with UIC2 Fab and taxol

SupramoleculeName: nanodisc reconstituted human ABCB1 in complex with UIC2 Fab and taxol
type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Supramolecule #3: UIC2 Fab

SupramoleculeName: UIC2 Fab / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Mus musculus (house mouse)

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.2 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE-PROPANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 2.1 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6fn1

Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 240262
FSC plot (resolution estimation)

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