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- EMDB-13059: Structure of ABCB1/P-glycoprotein in the presence of the CFTR pot... -

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Basic information

Entry
Database: EMDB / ID: EMD-13059
TitleStructure of ABCB1/P-glycoprotein in the presence of the CFTR potentiator ivacaftor
Map dataStructure of ABCB1/P-glycoprotein in the presence of the CFTR potentiator ivacaftor
Sample
  • Complex: Structure of ABCB1/P-glycoprotein in the presence of the CFTR potentiator ivacaftor
    • Protein or peptide: Multidrug resistance protein 1A
  • Ligand: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
KeywordsABCB1 / ABC Transporters / Membrane Proteins / Ivacaftor / MDR1 / Multidrug resistance / cryo-em / MEMBRANE PROTEIN
Function / homology
Function and homology information


Atorvastatin ADME / aldosterone secretion / Prednisone ADME / neural tissue regeneration / cellular response to nonylphenol / cellular response to borneol / response to codeine / cellular response to mycotoxin / daunorubicin transport / positive regulation of response to drug ...Atorvastatin ADME / aldosterone secretion / Prednisone ADME / neural tissue regeneration / cellular response to nonylphenol / cellular response to borneol / response to codeine / cellular response to mycotoxin / daunorubicin transport / positive regulation of response to drug / terpenoid transport / ceramide floppase activity / regulation of intestinal absorption / cellular response to external biotic stimulus / response to cyclosporin A / response to antineoplastic agent / positive regulation of establishment of Sertoli cell barrier / negative regulation of sensory perception of pain / carboxylic acid transmembrane transport / floppase activity / ceramide translocation / ABC-family proteins mediated transport / response to quercetin / carboxylic acid transmembrane transporter activity / establishment of blood-retinal barrier / protein localization to bicellular tight junction / phosphatidylethanolamine flippase activity / phosphatidylcholine floppase activity / xenobiotic transport across blood-brain barrier / response to thyroxine / intercellular canaliculus / establishment of blood-brain barrier / export across plasma membrane / cardiac muscle cell differentiation / P-type phospholipid transporter / xenobiotic detoxification by transmembrane export across the plasma membrane / transepithelial transport / cellular response to L-glutamate / ABC-type xenobiotic transporter / adult heart development / response to vitamin A / response to vitamin D / response to glucagon / intestinal absorption / response to glycoside / response to alcohol / ABC-type xenobiotic transporter activity / phospholipid translocation / cellular hyperosmotic salinity response / cellular response to alkaloid / female gonad development / maintenance of blood-brain barrier / cellular response to antibiotic / exploration behavior / ATPase-coupled transmembrane transporter activity / efflux transmembrane transporter activity / xenobiotic transmembrane transporter activity / cellular response to dexamethasone stimulus / response to cadmium ion / transmembrane transporter activity / xenobiotic transport / lactation / response to progesterone / proteasomal protein catabolic process / neurogenesis / regulation of chloride transport / placenta development / stem cell proliferation / cellular response to estradiol stimulus / brush border membrane / female pregnancy / circadian rhythm / G2/M transition of mitotic cell cycle / response to toxic substance / cellular response to tumor necrosis factor / epidermal growth factor receptor signaling pathway / heart development / cellular response to lipopolysaccharide / gene expression / response to hypoxia / apical plasma membrane / response to xenobiotic stimulus / ubiquitin protein ligase binding / cell surface / ATP hydrolysis activity / 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 speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.4 Å
AuthorsFord RC / Barbieri A
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Membranes (Basel) / Year: 2021
Title: Structure of ABCB1/P-Glycoprotein in the Presence of the CFTR Potentiator Ivacaftor.
Authors: Alessandro Barbieri / Nopnithi Thonghin / Talha Shafi / Stephen M Prince / Richard F Collins / Robert C Ford /
Abstract: ABCB1/P-glycoprotein is an ATP binding cassette transporter that is involved in the clearance of xenobiotics, and it affects the disposition of many drugs in the body. Conformational flexibility of ...ABCB1/P-glycoprotein is an ATP binding cassette transporter that is involved in the clearance of xenobiotics, and it affects the disposition of many drugs in the body. Conformational flexibility of the protein within the membrane is an intrinsic part of its mechanism of action, but this has made structural studies challenging. Here, we have studied different conformations of P-glycoprotein simultaneously in the presence of ivacaftor, a known competitive inhibitor. In order to conduct this, we used high contrast cryo-electron microscopy imaging with a Volta phase plate. We associate the presence of ivacaftor with the appearance of an additional density in one of the conformational states detected. The additional density is in the central aqueous cavity and is associated with a wider separation of the two halves of the transporter in the inward-facing state. Conformational changes to the nucleotide-binding domains are also observed and may help to explain the stimulation of ATPase activity that occurs when transported substrate is bound in many ATP binding cassette transporters.
History
DepositionJun 10, 2021-
Header (metadata) releaseDec 8, 2021-
Map releaseDec 8, 2021-
UpdateJul 17, 2024-
Current statusJul 17, 2024Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 1
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  • Surface view colored by cylindrical radius
  • Surface level: 1
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  • Surface view with fitted model
  • Atomic models: PDB-7otg
  • Surface level: 1
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7otg
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_13059.png

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Map

FileDownload / File: emd_13059.map.gz / Format: CCP4 / Size: 40.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationStructure of ABCB1/P-glycoprotein in the presence of the CFTR potentiator ivacaftor
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.04 Å/pix.
x 220 pix.
= 229.46 Å		1.04 Å/pix.
x 220 pix.
= 229.46 Å		1.04 Å/pix.
x 220 pix.
= 229.46 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.043 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.67 / Movie #1: 1
Minimum - Maximum-2.0847585 - 4.3316174
Average (Standard dev.)0.0068661105 (±0.19081847)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions220220220
Spacing220220220
CellA=B=C: 229.45999 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0431.0431.043
M x/y/z220220220
origin x/y/z0.0000.0000.000
length x/y/z229.460229.460229.460
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS220220220
D min/max/mean-2.0854.3320.007

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Supplemental data

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Sample components

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Entire : Structure of ABCB1/P-glycoprotein in the presence of the CFTR pot...

EntireName: Structure of ABCB1/P-glycoprotein in the presence of the CFTR potentiator ivacaftor
Components
  • Complex: Structure of ABCB1/P-glycoprotein in the presence of the CFTR potentiator ivacaftor
    • Protein or peptide: Multidrug resistance protein 1A
  • Ligand: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

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Supramolecule #1: Structure of ABCB1/P-glycoprotein in the presence of the CFTR pot...

SupramoleculeName: Structure of ABCB1/P-glycoprotein in the presence of the CFTR potentiator ivacaftor
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Multidrug resistance protein 1A

MacromoleculeName: Multidrug resistance protein 1A / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: ec: 3.6.3.44
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 141.877875 KDa
Recombinant expressionOrganism: Komagataella pastoris (fungus)
SequenceString: MELEEDLKGR ADKNFSKMGK KSKKEKKEKK PAVSVLTMFR YAGWLDRLYM LVGTLAAIIH GVALPLMMLI FGDMTDSFAS VGNVSKNST NMSEADKRAM FAKLEEEMTT YAYYYTGIGA GVLIVAYIQV SFWCLAAGRQ IHKIRQKFFH AIMNQEIGWF D VHDVGELN ...String:
MELEEDLKGR ADKNFSKMGK KSKKEKKEKK PAVSVLTMFR YAGWLDRLYM LVGTLAAIIH GVALPLMMLI FGDMTDSFAS VGNVSKNST NMSEADKRAM FAKLEEEMTT YAYYYTGIGA GVLIVAYIQV SFWCLAAGRQ IHKIRQKFFH AIMNQEIGWF D VHDVGELN TRLTDDVSKI NEGIGDKIGM FFQAMATFFG GFIIGFTRGW KLTLVILAIS PVLGLSAGIW AKILSSFTDK EL HAYAKAG AVAEEVLAAI RTVIAFGGQK KELERYNNNL EEAKRLGIKK AITANISMGA AFLLIYASYA LAFWYGTSLV ISK EYSIGQ VLTVFFSVLI GAFSVGQASP NIEAFANARG AAYEVFKIID NKPSIDSFSK SGHKPDNIQG NLEFKNIHFS YPSR KEVQI LKGLNLKVKS GQTVALVGNS GCGKSTTVQL MQRLYDPLDG MVSIDGQDIR TINVRYLREI IGVVSQEPVL FATTI AENI RYGREDVTMD EIEKAVKEAN AYDFIMKLPH QFDTLVGERG AQLSGGQKQR IAIARALVRN PKILLLDEAT SALDTE SEA VVQAALDKAR EGRTTIVIAH RLSTVRNADV IAGFDGGVIV EQGNHDELMR EKGIYFKLVM TQTAGNEIEL GNEACKS KD EIDNLDMSSK DSGSSLIRRR STRKSICGPH DQDRKLSTKE ALDEDVPPAS FWRILKLNST EWPYFVVGIF CAIINGGL Q PAFSVIFSKV VGVFTNGGPP ETQRQNSNLF SLLFLILGII SFITFFLQGF TFGKAGEILT KRLRYMVFKS MLRQDVSWF DDPKNTTGAL TTRLANDAAQ VKGATGSRLA VIFQNIANLG TGIIISLIYG WQLTLLLLAI VPIIAIAGVV EMKMLSGQAL KDKKELEGS GKIATEAIEN FRTVVSLTRE QKFETMYAQS LQIPYRNAMK KAHVFGITFS FTQAMMYFSY AACFRFGAYL V TQQLMTFE NVLLVFSAIV FGAMAVGQVS SFAPDYAKAT VSASHIIRII EKTPEIDSYS TQGLKPNMLE GNVQFSGVVF NY PTRPSIP VLQGLSLEVK KGQTLALVGS SGCGKSTVVQ LLERFYDPMA GSVFLDGKEI KQLNVQWLRA QLGIVSQEPI LFD CSIAEN IAYGDNSRVV SYEEIVRAAK EANIHQFIDS LPDKYNTRVG DKGTQLSGGQ KQRIAIARAL VRQPHILLLD EATS ALDTE SEKVVQEALD KAREGRTCIV IAHRLSTIQN ADLIVVIQNG KVKEHGTHQQ LLAQKGIYFS MVSVQAGAKR SLEHH HHHH

UniProtKB: ATP-dependent translocase ABCB1

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Macromolecule #2: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-...

MacromoleculeName: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
type: ligand / ID: 2 / Number of copies: 1 / Formula: VX7
Molecular weightTheoretical: 392.491 Da
Chemical component information

ChemComp-VX7:
N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide / medication*YM

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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

Concentration1.1 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsPhase plate: VOLTA PHASE PLATE / Spherical aberration corrector: 2.7
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 64.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 317000
Startup modelType of model: NONE
Final reconstructionNumber classes used: 1 / Resolution.type: BY AUTHOR / Resolution: 5.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 104000
Initial angle assignmentType: OTHER / Software - Name: cisTEM
Final angle assignmentType: OTHER / Software - Name: cisTEM
Final 3D classificationNumber classes: 1

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