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- EMDB-45932: HUMAN ABCB1 in SapNPs in complex with Zosuquidar -

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Basic information

Entry
Database: EMDB / ID: EMD-45932
TitleHUMAN ABCB1 in SapNPs in complex with Zosuquidar
Map data
Sample
  • Complex: HUMAN ABCB1 in SapNPs in complex with Zosuquidar
    • Protein or peptide: ATP binding cassette (ABC) transporter ABCB1 or P-glycoprotein (P-gp)
KeywordsABCB1 / P-gp / nanoparticle / saposinA / Inhibitor / zosuquidar / MEMBRANE 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: 3.6 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 26, 2024-
Header (metadata) releaseJan 22, 2025-
Map releaseJan 22, 2025-
UpdateMar 5, 2025-
Current statusMar 5, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_45932.png

Downloads & links

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Map

FileDownload / File: emd_45932.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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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

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.996 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.005
Minimum - Maximum-0.01995121 - 0.03654852
Average (Standard dev.)0.00003039977 (±0.0010559607)
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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Half map: #1

Fileemd_45932_half_map_1.map
Projections & Slices
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Half map: #2

Fileemd_45932_half_map_2.map
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Sample components

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Entire : HUMAN ABCB1 in SapNPs in complex with Zosuquidar

EntireName: HUMAN ABCB1 in SapNPs in complex with Zosuquidar
Components
  • Complex: HUMAN ABCB1 in SapNPs in complex with Zosuquidar
    • Protein or peptide: ATP binding cassette (ABC) transporter ABCB1 or P-glycoprotein (P-gp)

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Supramolecule #1: HUMAN ABCB1 in SapNPs in complex with Zosuquidar

SupramoleculeName: HUMAN ABCB1 in SapNPs in complex with Zosuquidar / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: ATP binding cassette (ABC) transporter ABCB1 or P-glycoprotein (P-gp)

MacromoleculeName: ATP binding cassette (ABC) transporter ABCB1 or P-glycoprotein (P-gp)
type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDLEGDRNGG AKKKNFFKLN NKSEKDKKEK KPTVSVFSMF RYSNWLDKLY MVVGTLAAII HGAGLPLMML VFGEMTDIFA NAGNLEDLMS NITNRSDIND TGFFMNLEED MTRYAYYYSG IGAGVLVAAY IQVSFWCLAA GRQIHKIRKQ FFHAIMRQEI GWFDVHDVGE ...String:
MDLEGDRNGG AKKKNFFKLN NKSEKDKKEK KPTVSVFSMF RYSNWLDKLY MVVGTLAAII HGAGLPLMML VFGEMTDIFA NAGNLEDLMS NITNRSDIND TGFFMNLEED MTRYAYYYSG IGAGVLVAAY IQVSFWCLAA GRQIHKIRKQ FFHAIMRQEI GWFDVHDVGE LNTRLTDDVS KINEGIGDKI GMFFQSMATF FTGFIVGFTR GWKLTLVILA ISPVLGLSAA VWAKILSSFT DKELLAYAKA GAVAEEVLAA IRTVIAFGGQ KKELERYNKN LEEAKRIGIK KAITANISIG AAFLLIYASY ALAFWYGTTL VLSGEYSIGQ VLTVFFSVLI GAFSVGQASP SIEAFANARG AAYEIFKIID NKPSIDSYSK SGHKPDNIKG NLEFRNVHFS YPSRKEVKIL KGLNLKVQSG QTVALVGNSG CGKSTTVQLM QRLYDPTEGM VSVDGQDIRT INVRFLREII GVVSQEPVLF ATTIAENIRY GRENVTMDEI EKAVKEANAY DFIMKLPHKF DTLVGERGAQ LSGGQKQRIA IARALVRNPK ILLLDEATSA LDTESEAVVQ VALDKARKGR TTIVIAHRLS TVRNADVIAG FDDGVIVEKG NHDELMKEKG IYFKLVTMQT AGNEVELENA ADESKSEIDA LEMSSNDSRS SLIRKRSTRR SVRGSQAQDR KLSTKEALDE SIPPVSFWRI MKLNLTEWPY FVVGVFCAII NGGLQPAFAI IFSKIIGVFT RIDDPETKRQ NSNLFSLLFL ALGIISFITF FLQGFTFGKA GEILTKRLRY MVFRSMLRQD VSWFDDPKNT TGALTTRLAN DAAQVKGAIG SRLAVITQNI ANLGTGIIIS FIYGWQLTLL LLAIVPIIAI AGVVEMKMLS GQALKDKKEL EGSGKIATEA IENFRTVVSL TQEQKFEHMY AQSLQVPYRN SLRKAHIFGI TFSFTQAMMY FSYAGCFRFG AYLVAHKLMS FEDVLLVFSA VVFGAMAVGQ VSSFAPDYAK AKISAAHIIM IIEKTPLIDS YSTEGLMPNT LEGNVTFGEV VFNYPTRPDI PVLQGLSLEV KKGQTLALVG SSGCGKSTVV QLLERFYDPL AGKVLLDGKE IKRLNVQWLR AHLGIVSQEP ILFDCSIAEN IAYGDNSRVV SQEEIVRAAK EANIHAFIES LPNKYSTKVG DKGTQLSGGQ KQRIAIARAL VRQPHILLLD EATSALDTES EKVVQEALDK AREGRTCIVI AHRLSTIQNA DLIVVFQNGR VKEHGTHQQL LAQKGIYFSM VSVQAGTKRQ

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

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

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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: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 373279
Initial angle assignmentType: NOT APPLICABLE / Software - Name: RELION
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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