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- EMDB-4539: Nanodisc reconstituted human ABCB1 in complex with UIC2 fab and taxol -

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Basic information

Entry
Database: EMDB / ID: 4539
TitleNanodisc reconstituted human ABCB1 in complex with UIC2 fab and taxol
Map dataPostprocessed map of nanodisc reconstituted human ABCB1 in complex with UIC2 Fab and taxol
SampleNanodisc reconstituted human ABCB1 in complex with UIC2 Fab and taxol
  • nanodisc reconstituted human ABCB1
  • UIC2 Fab
  • Multidrug resistance protein 1Multiple drug resistance
  • UIC2 Fab lightchain
  • UIC2 Fab heavy chain
  • (ligand) x 4
Function / homologyType I protein exporter / ABC transporter-like / ABC-family proteins mediated transport / Abacavir transmembrane transport / ABC transporter integral membrane type-1 fused domain profile. / ATP-binding cassette, ABC transporter-type domain profile. / ABC transporters family signature. / ABC transporter transmembrane region / ABC transporter / ABC transporter type 1, transmembrane domain superfamily ...Type I protein exporter / ABC transporter-like / ABC-family proteins mediated transport / Abacavir transmembrane transport / ABC transporter integral membrane type-1 fused domain profile. / ATP-binding cassette, ABC transporter-type domain profile. / ABC transporters family signature. / ABC transporter transmembrane region / ABC transporter / ABC transporter type 1, transmembrane domain superfamily / Multidrug resistance protein 1 / P-loop containing nucleoside triphosphate hydrolase / ABC transporter, conserved site / ABC transporter type 1, transmembrane domain / AAA+ ATPase domain / ceramide translocation / ceramide-translocating ATPase activity / positive regulation of anion channel activity / phosphatidylethanolamine-translocating ATPase activity / ABC-type xenobiotic transporter / phosphatidylcholine-translocating ATPase activity / regulation of response to osmotic stress / phospholipid translocation / xenobiotic transmembrane transporting ATPase activity / stem cell proliferation / ATPase activity, coupled to transmembrane movement of substances / transporter activity / regulation of chloride transport / transmembrane transport / apical plasma membrane / G2/M transition of mitotic cell cycle / response to drug / cell surface / extracellular exosome / membrane / integral component of membrane / ATP binding / plasma membrane / Multidrug resistance protein 1
Function and homology information
SourceHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / 3.6 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.
Validation ReportPDB-ID: 6qex

SummaryFull reportAbout validation report
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: 0.01
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by height
  • Surface level: 0.01
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: : PDB-6qex
  • Surface level: 0.01
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

Fileemd_4539.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:0.008 (by author), 0.01 (movie #1):
Minimum - Maximum-0.088010296 - 0.14215547
Average (Standard dev.)-0.0000034037519 (0.0019025864)
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-0.0880.142-0.000

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Supplemental data

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Sample components

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Entire Nanodisc reconstituted human ABCB1 in complex with UIC2 Fab and taxol

EntireName: Nanodisc reconstituted human ABCB1 in complex with UIC2 Fab and taxol
Number of components: 10

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Component #1: protein, Nanodisc reconstituted human ABCB1 in complex with UIC2 ...

ProteinName: Nanodisc reconstituted human ABCB1 in complex with UIC2 Fab and taxol
Recombinant expression: No
MassExperimental: 200 kDa

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Component #2: protein, nanodisc reconstituted human ABCB1

ProteinName: nanodisc reconstituted human ABCB1 / 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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Component #4: protein, Multidrug resistance protein 1

ProteinName: Multidrug resistance protein 1Multiple drug resistance
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 141.628781 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #5: protein, UIC2 Fab lightchain

ProteinName: UIC2 Fab lightchain / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 24.321039 kDa
SourceSpecies: Mus musculus (house mouse)

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Component #6: protein, UIC2 Fab heavy chain

ProteinName: UIC2 Fab heavy chain / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 24.381281 kDa
SourceSpecies: Mus musculus (house mouse)

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Component #7: ligand, N-ACETYL-D-GLUCOSAMINE

LigandName: N-ACETYL-D-GLUCOSAMINEN-Acetylglucosamine / Number of Copies: 3 / Recombinant expression: No
MassTheoretical: 0.221208 kDa

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Component #8: ligand, CHOLESTEROL

LigandName: CHOLESTEROL / Number of Copies: 16 / Recombinant expression: No
MassTheoretical: 0.386654 kDa

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Component #9: ligand, TAXOL

LigandName: TAXOLPaclitaxel / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 0.853906 kDa

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Component #10: ligand, 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE

LigandName: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 0.748065 kDa

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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 / Number of projections: 262191
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF
FSC plot
(resolution estimation)

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Atomic model buiding

Output model

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