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- EMDB-7325: Molecular structure of human P-glycoprotein in the ATP-bound, out... -

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Basic information

Entry
Database: EMDB / ID: EMD-7325
TitleMolecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation
Map datab-factor sharpening 100
Sample
  • Complex: Human P-glycoprotein E556Q, E1201Q
    • Protein or peptide: Multidrug resistance protein 1
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
KeywordsABC transporter / ABCB1 / P-glycoprotein / cryo-EM / multidrug resistance / Structural Genomics / PSI-2 / Protein Structure Initiative / TRANSPORT PROTEIN
Function / homology
Function and homology information


carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / terpenoid transport / ceramide floppase activity / ceramide translocation / floppase activity / Abacavir transmembrane transport / external side of apical plasma membrane / phosphatidylethanolamine flippase activity / phosphatidylcholine floppase activity ...carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / terpenoid transport / ceramide floppase activity / ceramide translocation / floppase activity / Abacavir transmembrane transport / external side of apical plasma membrane / phosphatidylethanolamine flippase activity / phosphatidylcholine floppase activity / Atorvastatin ADME / xenobiotic transport across blood-brain barrier / xenobiotic detoxification by transmembrane export across the plasma membrane / transepithelial transport / export across plasma membrane / P-type phospholipid transporter / ABC-type xenobiotic transporter / ABC-type xenobiotic transporter activity / phospholipid translocation / Prednisone ADME / efflux transmembrane transporter activity / transmembrane transporter activity / xenobiotic transmembrane transporter activity / ATPase-coupled transmembrane transporter activity / transport across blood-brain barrier / xenobiotic metabolic process / regulation of chloride transport / stem cell proliferation / ABC-family proteins mediated transport / transmembrane transport / G2/M transition of mitotic cell cycle / apical plasma membrane / response to xenobiotic stimulus / ubiquitin protein ligase binding / cell surface / ATP hydrolysis activity / extracellular exosome / ATP binding / membrane / plasma membrane / cytoplasm
Similarity search - Function
Type 1 protein exporter / ABC transporter transmembrane region / ABC transporter type 1, transmembrane domain / ABC transporter integral membrane type-1 fused domain profile. / ABC transporter type 1, transmembrane domain superfamily / ABC transporter-like, conserved site / ABC transporters family signature. / ABC transporter / ABC transporter-like, ATP-binding domain / ATP-binding cassette, ABC transporter-type domain profile. ...Type 1 protein exporter / ABC transporter transmembrane region / ABC transporter type 1, transmembrane domain / ABC transporter integral membrane type-1 fused domain profile. / ABC transporter type 1, transmembrane domain superfamily / ABC transporter-like, conserved site / ABC transporters family signature. / ABC transporter / ABC transporter-like, ATP-binding domain / ATP-binding cassette, ABC transporter-type domain profile. / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ATP-dependent translocase ABCB1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsKim YJ / Chen J
Funding support United States, 1 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Science / Year: 2018
Title: Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation.
Authors: Youngjin Kim / Jue Chen /
Abstract: The multidrug transporter permeability (P)-glycoprotein is an adenosine triphosphate (ATP)-binding cassette exporter responsible for clinical resistance to chemotherapy. P-glycoprotein extrudes toxic ...The multidrug transporter permeability (P)-glycoprotein is an adenosine triphosphate (ATP)-binding cassette exporter responsible for clinical resistance to chemotherapy. P-glycoprotein extrudes toxic molecules and drugs from cells through ATP-powered conformational changes. Despite decades of effort, only the structures of the inward-facing conformation of P-glycoprotein are available. Here we present the structure of human P-glycoprotein in the outward-facing conformation, determined by cryo-electron microscopy at 3.4-angstrom resolution. The two nucleotide-binding domains form a closed dimer occluding two ATP molecules. The drug-binding cavity observed in the inward-facing structures is reorientated toward the extracellular space and compressed to preclude substrate binding. This observation indicates that ATP binding, not hydrolysis, promotes substrate release. The structure evokes a model in which the dynamic nature of P-glycoprotein enables translocation of a large variety of substrates.
History
DepositionJan 2, 2018-
Header (metadata) releaseJan 31, 2018-
Map releaseJan 31, 2018-
UpdateMar 13, 2024-
Current statusMar 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 1.6
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by height
  • Surface level: 1.6
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6c0v
  • Surface level: 1.6
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_7325.png

Downloads & links

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Map

FileDownload / File: emd_7325.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationb-factor sharpening 100
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 384 pix.
= 322.56 Å		0.84 Å/pix.
x 384 pix.
= 322.56 Å		0.84 Å/pix.
x 384 pix.
= 322.56 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

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.6 / Movie #1: 1.6
Minimum - Maximum-5.3812027 - 8.942655999999999
Average (Standard dev.)0.0045612296 (±0.18939726)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 322.56 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.840.840.84
M x/y/z384384384
origin x/y/z0.0000.0000.000
length x/y/z322.560322.560322.560
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ281156
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS384384384
D min/max/mean-5.3818.9430.005

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Supplemental data

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Additional map: original map

Fileemd_7325_additional.map
Annotationoriginal map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human P-glycoprotein E556Q, E1201Q

EntireName: Human P-glycoprotein E556Q, E1201Q
Components
  • Complex: Human P-glycoprotein E556Q, E1201Q
    • Protein or peptide: Multidrug resistance protein 1
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION

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Supramolecule #1: Human P-glycoprotein E556Q, E1201Q

SupramoleculeName: Human P-glycoprotein E556Q, E1201Q / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 141 KDa

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Macromolecule #1: Multidrug resistance protein 1

MacromoleculeName: Multidrug resistance protein 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: ec: 3.6.3.44
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 142.660922 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDLEGDRNGG AKKKNFFKLN NKSEKDKKEK KPTVSVFSMF RYSNWLDKLY MVVGTLAAII HGAGLPLMML VFGEMTDIFA NAGNLEDLM SNITNRSDIN DTGFFMNLEE DMTRYAYYYS GIGAGVLVAA YIQVSFWCLA AGRQIHKIRK QFFHAIMRQE I GWFDVHDV ...String:
MDLEGDRNGG AKKKNFFKLN NKSEKDKKEK KPTVSVFSMF RYSNWLDKLY MVVGTLAAII HGAGLPLMML VFGEMTDIFA NAGNLEDLM SNITNRSDIN DTGFFMNLEE DMTRYAYYYS GIGAGVLVAA YIQVSFWCLA AGRQIHKIRK QFFHAIMRQE I GWFDVHDV GELNTRLTDD VSKINEGIGD KIGMFFQSMA TFFTGFIVGF TRGWKLTLVI LAISPVLGLS AAVWAKILSS FT DKELLAY AKAGAVAEEV LAAIRTVIAF GGQKKELERY NKNLEEAKRI GIKKAITANI SIGAAFLLIY ASYALAFWYG TTL VLSGEY SIGQVLTVFF SVLIGAFSVG QASPSIEAFA NARGAAYEIF KIIDNKPSID SYSKSGHKPD NIKGNLEFRN VHFS YPSRK EVKILKGLNL KVQSGQTVAL VGNSGCGKST TVQLMQRLYD PTEGMVSVDG QDIRTINVRF LREIIGVVSQ EPVLF ATTI AENIRYGREN VTMDEIEKAV KEANAYDFIM KLPHKFDTLV GERGAQLSGG QKQRIAIARA LVRNPKILLL DQATSA LDT ESEAVVQVAL DKARKGRTTI VIAHRLSTVR NADVIAGFDD GVIVEKGNHD ELMKEKGIYF KLVTMQTAGN EVELENA AD ESKSEIDALE MSSNDSRSSL IRKRSTRRSV RGSQAQDRKL STKEALDESI PPVSFWRIMK LNLTEWPYFV VGVFCAII N GGLQPAFAII FSKIIGVFTR IDDPETKRQN SNLFSLLFLA LGIISFITFF LQGFTFGKAG EILTKRLRYM VFRSMLRQD VSWFDDPKNT TGALTTRLAN DAAQVKGAIG SRLAVITQNI ANLGTGIIIS FIYGWQLTLL LLAIVPIIAI AGVVEMKMLS GQALKDKKE LEGSGKIATE AIENFRTVVS LTQEQKFEHM YAQSLQVPYR NSLRKAHIFG ITFSFTQAMM YFSYAGCFRF G AYLVAHKL MSFEDVLLVF SAVVFGAMAV GQVSSFAPDY AKAKISAAHI IMIIEKTPLI DSYSTEGLMP NTLEGNVTFG EV VFNYPTR PDIPVLQGLS LEVKKGQTLA LVGSSGCGKS TVVQLLERFY DPLAGKVLLD GKEIKRLNVQ WLRAHLGIVS QEP ILFDCS IAENIAYGDN SRVVSQEEIV RAAKEANIHA FIESLPNKYS TKVGDKGTQL SGGQKQRIAI ARALVRQPHI LLLD QATSA LDTESEKVVQ EALDKAREGR TCIVIAHRLS TIQNADLIVV FQNGRVKEHG THQQLLAQKG IYFSMVSVQA GTKRQ SNSL EVLFQ

UniProtKB: ATP-dependent translocase ABCB1

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Macromolecule #2: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 2 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

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Macromolecule #3: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 3 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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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

Concentration5.0 mg/mL
BufferpH: 7.5
Component:
ConcentrationName
200.0 mMNaCl
20.0 mMTris
10.0 mMMgCl2
10.0 mMATP
3.0 mMFos-Choline-8, fluornate
150.0 uMVinblastine
0.05 %DDM
0.005 %Cholesteryl hemisuccinate
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 15 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
TemperatureMin: 80.0 K / Max: 100.0 K
Specialist opticsEnergy filter - Lower energy threshold: 10 eV / Energy filter - Upper energy threshold: 10 eV
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Dimensions - Width: 3838 pixel / Digitization - Dimensions - Height: 3710 pixel / Digitization - Frames/image: 1-50 / Number grids imaged: 2 / Number real images: 5747 / Average exposure time: 7.0 sec. / Average electron dose: 80.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 143451
Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: FREALIGN / Number images used: 143451
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION (ver. 1.4)
Final angle assignmentType: PROJECTION MATCHING / Software - Name: FREALIGN

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Atomic model buiding 1

RefinementSpace: RECIPROCAL / Protocol: FLEXIBLE FIT
Output model

PDB-6c0v:
Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation

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