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- EMDB-40341: CryoEM structure of P-Glycoprotein in inward facing state 2 with ... -

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Basic information

Entry
Database: EMDB / ID: EMD-40341
TitleCryoEM structure of P-Glycoprotein in inward facing state 2 with vinblastine
Map dataCryoEM structure of P-Glycoprotein in inward facing state 2 with vinblastine
Sample
  • Complex: CryoEM structure of P-Glycoprotein in inward facing state 2 with vinblastine
    • Protein or peptide: P-glycoprotein
Keywordsmultidrug resistance / ABC transporter / membrane protein / transporter / TRANSPORT PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.5 Å
AuthorsCulbertson A / Liao M
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
CitationJournal: Nat Commun / Year: 2025
Title: Cryo-EM of human P-glycoprotein reveals an intermediate occluded conformation during active drug transport.
Authors: Alan T Culbertson / Maofu Liao /
Abstract: P-glycoprotein (Pgp) is an important human multidrug transporter that contributes to pharmacokinetics and multidrug resistance. Despite decades of study, the conformation transition cycle of Pgp ...P-glycoprotein (Pgp) is an important human multidrug transporter that contributes to pharmacokinetics and multidrug resistance. Despite decades of study, the conformation transition cycle of Pgp undergoing active drug transport is not defined, thus the precise relevance of all available Pgp structures to uninterrupted multidrug transport remains unclear. Here, we use cryo-EM of membrane-embedded human Pgp under continuous turnover conditions to analyze the conformational ensembles of Pgp transporting distinct substrates. These results delineate multiple conformations including inward-facing and closed conformations, highlighting the occluded conformation as a critical intermediate state between transporter closure and substrate release. A combination of structural, functional, and computational studies reveals the transmembrane helices 4 and 10 undergoing drastic rearrangement to coordinate substrate binding, occlusion, and release, and identifies a peripheral site involved in substrate capture and Pgp inhibition. Together, our results provide a set of snapshots of Pgp undergoing continuous drug transport, unveiling the intricate interplay between transporter dynamics and drug movement, and shed light on the mechanism of polyspecificity.
History
DepositionApr 4, 2023-
Header (metadata) releaseApr 23, 2025-
Map releaseApr 23, 2025-
UpdateApr 23, 2025-
Current statusApr 23, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40341.png

Downloads & links

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Map

FileDownload / File: emd_40341.map.gz / Format: CCP4 / Size: 27 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryoEM structure of P-Glycoprotein in inward facing state 2 with vinblastine
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 192 pix.
= 203.52 Å		1.06 Å/pix.
x 192 pix.
= 203.52 Å		1.06 Å/pix.
x 192 pix.
= 203.52 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: 0.06
Minimum - Maximum-0.10069013 - 0.17007208
Average (Standard dev.)0.00025160107 (±0.010490833)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-96-96-96
Dimensions192192192
Spacing192192192
CellA=B=C: 203.51999 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: CryoEM structure of P-Glycoprotein in inward facing state...

Fileemd_40341_half_map_1.map
AnnotationCryoEM structure of P-Glycoprotein in inward facing state 2 with vinblastine
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: CryoEM structure of P-Glycoprotein in inward facing state...

Fileemd_40341_half_map_2.map
AnnotationCryoEM structure of P-Glycoprotein in inward facing state 2 with vinblastine
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : CryoEM structure of P-Glycoprotein in inward facing state 2 with ...

EntireName: CryoEM structure of P-Glycoprotein in inward facing state 2 with vinblastine
Components
  • Complex: CryoEM structure of P-Glycoprotein in inward facing state 2 with vinblastine
    • Protein or peptide: P-glycoprotein

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Supramolecule #1: CryoEM structure of P-Glycoprotein in inward facing state 2 with ...

SupramoleculeName: CryoEM structure of P-Glycoprotein in inward facing state 2 with vinblastine
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: P-glycoprotein

MacromoleculeName: P-glycoprotein / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: 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

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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: 7.4
Component:
ConcentrationNameFormula
50.0 mMTris-HCl
150.0 mMSodium ChlorideNaCl
0.1 mMTCEP
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 2 / Number real images: 6338 / Average exposure time: 3.5 sec. / Average electron dose: 53.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 81000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 19023
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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