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- EMDB-45904: SapNP Reconstituted Human ABCB1 bound to Taxol in presence of ATP -

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Basic information

Entry
Database: EMDB / ID: EMD-45904
TitleSapNP Reconstituted Human ABCB1 bound to Taxol in presence of ATP
Map datahuman ABCB1 reconstituted in SapNPs with BPL/Chol in complex with Taxol and ATP/Mg postprocessed map
Sample
  • Complex: Human ABCB1 in complex with substrate (taxol) in presence of ATP
    • Protein or peptide: ATP-dependent translocase ABCB1
  • Ligand: UNKNOWN BRANCHED FRAGMENT OF PHOSPHOLIPID
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: TAXOL
KeywordsABCB1 / P-gp / substrate bound / nanoparticle / saposin A / taxol bound / MEMBRANE PROTEIN / php / MDR1 / TRANSLOCASE
Function / homology
Function and homology information


carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / terpenoid transport / ceramide floppase activity / floppase activity / ceramide translocation / Abacavir transmembrane transport / external side of apical plasma membrane / Atorvastatin ADME / phosphatidylethanolamine flippase activity ...carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / terpenoid transport / ceramide floppase activity / floppase activity / ceramide translocation / Abacavir transmembrane transport / external side of apical plasma membrane / Atorvastatin ADME / phosphatidylethanolamine flippase activity / phosphatidylcholine floppase activity / xenobiotic detoxification by transmembrane export across the plasma membrane / xenobiotic transport across blood-brain barrier / 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 / xenobiotic transmembrane transporter activity / 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 / response to xenobiotic stimulus / apical plasma membrane / 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: 3.9 Å
AuthorsKurre D / Alam A
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1R01GM146906 United States
CitationJournal: EMBO J / Year: 2025
Title: Structural insights into binding-site access and ligand recognition by human ABCB1.
Authors: Devanshu Kurre / Phuoc X Dang / Le T M Le / Varun V Gadkari / Amer Alam /
Abstract: ABCB1 is a broad-spectrum efflux pump central to cellular drug handling and multidrug resistance in humans. However, how it is able to recognize and transport a wide range of diverse substrates ...ABCB1 is a broad-spectrum efflux pump central to cellular drug handling and multidrug resistance in humans. However, how it is able to recognize and transport a wide range of diverse substrates remains poorly understood. Here we present cryo-EM structures of lipid-embedded human ABCB1 in conformationally distinct apo-, substrate-bound, inhibitor-bound, and nucleotide-trapped states at 3.4-3.9 Å resolution, in the absence of stabilizing antibodies or mutations. The substrate-binding site is located within one half of the molecule and, in the apo state, is obstructed by the transmembrane helix (TM) 4. Substrate and inhibitor binding are distinguished by major TM rearrangements and their ligand binding chemistry, with TM4 playing a central role in all conformational transitions. Furthermore, our data identify secondary structure-breaking residues that impart localized TM flexibility and asymmetry between the two transmembrane domains. The resulting structural changes and lipid interactions that are induced by substrate and inhibitor binding can predict substrate-binding profiles and may direct ABCB1 inhibitor design.
History
DepositionJul 25, 2024-
Header (metadata) releaseJan 22, 2025-
Map releaseJan 22, 2025-
UpdateJan 22, 2025-
Current statusJan 22, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_45904.png

Downloads & links

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Map

FileDownload / File: emd_45904.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationhuman ABCB1 reconstituted in SapNPs with BPL/Chol in complex with Taxol and ATP/Mg postprocessed map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1 Å/pix.
x 256 pix.
= 254.976 Å		1 Å/pix.
x 256 pix.
= 254.976 Å		1 Å/pix.
x 256 pix.
= 254.976 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.996 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.008
Minimum - Maximum-0.045435496 - 0.06863762
Average (Standard dev.)0.00001193565 (±0.0018476696)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 254.976 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: human ABCB1 reconstituted in SapNPs with BPL/Chol in...

Fileemd_45904_additional_1.map
Annotationhuman ABCB1 reconstituted in SapNPs with BPL/Chol in complex with Taxol and ATP/Mg Local Resolution filtered map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: human ABCB1 reconstituted in SapNPs with BPL/Chol in...

Fileemd_45904_half_map_1.map
Annotationhuman ABCB1 reconstituted in SapNPs with BPL/Chol in complex with Taxol and ATP/Mg - halfmap 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: human ABCB1 reconstituted in SapNPs with BPL/Chol in...

Fileemd_45904_half_map_2.map
Annotationhuman ABCB1 reconstituted in SapNPs with BPL/Chol in complex with Taxol and ATP/Mg halfmap 2
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 ABCB1 in complex with substrate (taxol) in presence of ATP

EntireName: Human ABCB1 in complex with substrate (taxol) in presence of ATP
Components
  • Complex: Human ABCB1 in complex with substrate (taxol) in presence of ATP
    • Protein or peptide: ATP-dependent translocase ABCB1
  • Ligand: UNKNOWN BRANCHED FRAGMENT OF PHOSPHOLIPID
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: TAXOL

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Supramolecule #1: Human ABCB1 in complex with substrate (taxol) in presence of ATP

SupramoleculeName: Human ABCB1 in complex with substrate (taxol) in presence of ATP
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: ATP-dependent translocase ABCB1

MacromoleculeName: ATP-dependent translocase ABCB1 / type: protein_or_peptide / ID: 1
Details: SapNP reconstituted human ABCB1 bound to taxol and ATP
Number of copies: 1 / Enantiomer: LEVO / EC number: ABC-type xenobiotic transporter
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 141.644781 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 DEATSA 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 EATSA LDTESEKVVQ EALDKAREGR TCIVIAHRLS TIQNADLIVV FQNGRVKEHG THQQLLAQKG IYFSMVSVQA GTKRQ

UniProtKB: ATP-dependent translocase ABCB1

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Macromolecule #2: UNKNOWN BRANCHED FRAGMENT OF PHOSPHOLIPID

MacromoleculeName: UNKNOWN BRANCHED FRAGMENT OF PHOSPHOLIPID / type: ligand / ID: 2 / Number of copies: 22 / Formula: UPL
Molecular weightTheoretical: 478.92 Da
Chemical component information

ChemComp-UPL:
UNKNOWN BRANCHED FRAGMENT OF PHOSPHOLIPID

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Macromolecule #3: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 3 / Number of copies: 1 / 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 #4: TAXOL

MacromoleculeName: TAXOL / type: ligand / ID: 4 / Number of copies: 1 / Formula: TA1
Molecular weightTheoretical: 853.906 Da
Chemical component information

ChemComp-TA1:
TAXOL / medication, chemotherapy*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

BufferpH: 7.5
Component:
ConcentrationNameFormula
25.0 mM4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
150.0 mMsodium chlorideNaCl

Details: 25mM HEPES (pH 7.5), 150mM NaCl
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
DetailsHuman ABCB1 reconstituted in BPL/Chol SapNPs

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOCONTINUUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 154538
Initial angle assignmentType: NOT APPLICABLE / Software - Name: RELION
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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