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- EMDB-4391: Structure of P-glycoprotein(ABCB1) in the post-hydrolytic state -

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Basic information

Entry
Database: EMDB / ID: EMD-4391
TitleStructure of P-glycoprotein(ABCB1) in the post-hydrolytic state
Map dataShows the additional density compared to the core domains as discussed in the manuscript. Corresponds to a volume enclosed of 160x10^3 Angstrom cubed.
Sample
  • Complex: mouse P-glycoprotein
    • Protein or peptide: Multidrug resistance protein 1A
KeywordsP-glycoprotein / ABCB1 / ATP-binding cassette / transporter / membrane protein / protein structure
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: 7.9 Å
AuthorsFord RC / Thonghin N
CitationJournal: BMC Struct Biol / Year: 2018
Title: Novel features in the structure of P-glycoprotein (ABCB1) in the post-hydrolytic state as determined at 7.9 Å resolution.
Authors: Nopnithi Thonghin / Richard F Collins / Alessandro Barbieri / Talha Shafi / Alistair Siebert / Robert C Ford /
Abstract: BACKGROUND: P-glycoprotein (ABCB1) is an ATP-binding cassette transporter that plays an important role in the clearance of drugs and xenobiotics and is associated with multi-drug resistance in cancer. ...BACKGROUND: P-glycoprotein (ABCB1) is an ATP-binding cassette transporter that plays an important role in the clearance of drugs and xenobiotics and is associated with multi-drug resistance in cancer. Although several P-glycoprotein structures are available, these are either at low resolution, or represent mutated and/or quiescent states of the protein.
RESULTS: In the post-hydrolytic state the structure of the wild-type protein has been resolved at about 8 Å resolution. The cytosolic nucleotide-binding domains (NBDs) are separated but ADP ...RESULTS: In the post-hydrolytic state the structure of the wild-type protein has been resolved at about 8 Å resolution. The cytosolic nucleotide-binding domains (NBDs) are separated but ADP remains bound, especially at the first NBD. Gaps in the transmembrane domains (TMDs) that connect to an inner hydrophilic cavity are filled by density emerging from the annular detergent micelle. The NBD-TMD linker is partly resolved, being located between the NBDs and close to the Signature regions involved in cooperative NBD dimerization. This, and the gap-filling detergent suggest steric impediment to NBD dimerization in the post-hydrolytic state. Two central regions of density lie in two predicted drug-binding sites, implying that the protein may adventitiously bind hydrophobic substances even in the post-hydrolytic state. The previously unresolved N-terminal extension was observed, and the data suggests these 30 residues interact with the headgroup region of the lipid bilayer.
CONCLUSION: The structural data imply that (i) a low basal ATPase activity is ensured by steric blockers of NBD dimerization and (ii) allocrite access to the central cavity may be structurally linked ...CONCLUSION: The structural data imply that (i) a low basal ATPase activity is ensured by steric blockers of NBD dimerization and (ii) allocrite access to the central cavity may be structurally linked to NBD dimerization, giving insights into the mechanism of drug-stimulation of P-glycoprotein activity.
History
DepositionApr 23, 2018-
Header (metadata) releaseMay 23, 2018-
Map releaseMay 23, 2018-
UpdateMay 15, 2024-
Current statusMay 15, 2024Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.03
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.03
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6gdi
  • Surface level: 0.03
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6q81
  • Surface level: 0.03
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6gdi
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_4391.png

Downloads & links

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Map

FileDownload / File: emd_4391.map.gz / Format: CCP4 / Size: 14.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationShows the additional density compared to the core domains as discussed in the manuscript. Corresponds to a volume enclosed of 160x10^3 Angstrom cubed.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 156 pix.
= 165.36 Å		1.06 Å/pix.
x 156 pix.
= 165.36 Å		1.06 Å/pix.
x 156 pix.
= 165.36 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.06 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.03 / Movie #1: 0.03
Minimum - Maximum-0.14932539 - 0.21956994
Average (Standard dev.)0.0027335607 (±0.012639964)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin303030
Dimensions156156156
Spacing156156156
CellA=B=C: 165.35999 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.061.061.06
M x/y/z156156156
origin x/y/z0.0000.0000.000
length x/y/z165.360165.360165.360
α/β/γ90.00090.00090.000
start NX/NY/NZ-383-383-383
NX/NY/NZ768768768
MAP C/R/S123
start NC/NR/NS303030
NC/NR/NS156156156
D min/max/mean-0.1490.2200.003

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Supplemental data

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Sample components

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Entire : mouse P-glycoprotein

EntireName: mouse P-glycoprotein
Components
  • Complex: mouse P-glycoprotein
    • Protein or peptide: Multidrug resistance protein 1A

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Supramolecule #1: mouse P-glycoprotein

SupramoleculeName: mouse P-glycoprotein / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
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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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
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 120 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 70.0 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

Startup modelType of model: OTHER
Final reconstructionNumber classes used: 18 / Resolution.type: BY AUTHOR / Resolution: 7.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 135357
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

4ksb


Chain - Chain ID: a / Chain - Residue range: 33-1271 / Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementProtocol: FLEXIBLE FIT
Output model

PDB-6gdi:
Structure of P-glycoprotein(ABCB1) in the post-hydrolytic state

PDB-6q81:
Structure of P-glycoprotein(ABCB1) in the post-hydrolytic state

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