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- EMDB-66043: Closed State of Apo-P-Glycoprotein. -

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Basic information

Entry
Database: EMDB / ID: EMD-66043
TitleClosed State of Apo-P-Glycoprotein.
Map data
Sample
  • Organelle or cellular component: ABCB1
KeywordsABCB1 / P-gp / MEMBRANE PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 7.17 Å
AuthorsHamaguchi-Suzuki N / Kanaoka Y / Ogasawara S / Murata T / Uchihashi T
Funding support Japan, 5 items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)JP21H000393 Japan
Japan Society for the Promotion of Science (JSPS)JP24K01309 Japan
Japan Society for the Promotion of Science (JSPS)JP24H00550 Japan
Ministry of Education, Culture, Sports, Science and Technology (Japan)JPMXP1323015482 Japan
Japan Agency for Medical Research and Development (AMED)JP25ama121013 Japan
CitationJournal: Int J Mol Sci / Year: 2025
Title: Visualizing the Functional Dynamics of P-Glycoprotein and Its Modulation by Elacridar via High-Speed Atomic Force Microscopy.
Authors: Yui Kanaoka / Norie Hamaguchi-Suzuki / Yuto Nonaka / Soichi Yamashita / Osamu Miyashita / Atsuyuki Ito / Satoshi Ogasawara / Florence Tama / Takeshi Murata / Takayuki Uchihashi /
Abstract: P-glycoprotein (P-gp) is an ATP-driven transporter that effluxes a wide range of xenobiotics from cells, and its overexpression is a primary cause of multidrug resistance (MDR) in cancer. It is well- ...P-glycoprotein (P-gp) is an ATP-driven transporter that effluxes a wide range of xenobiotics from cells, and its overexpression is a primary cause of multidrug resistance (MDR) in cancer. It is well-established that P-gp functions through conformational changes, yet its large-scale structural dynamics at work have been unexplored. Here, we directly visualized single P-gp molecules reconstituted in nanodiscs using high-speed atomic force microscopy (HS-AFM). The HS-AFM movies revealed that P-gp is intrinsically dynamic in its apo state, with its nucleotide-binding domains (NBDs) undergoing large, spontaneous opening and closing motions. However, addition of ATP stabilized a conformation characterized by NBD proximity with a strong tendency toward closure. We then leveraged this dynamic viewpoint to elucidate the relationship between Elacridar's function and the resulting structural dynamics of P-gp. Elacridar is designed to overcome multidrug resistance (MDR) in cancer and acts as a potent dual inhibitor of both P-gp and the Breast Cancer Resistance Protein (BCRP), effectively blocking the drug efflux function of these transporters. This inhibitor has suggested concentration-dependent function: it is effluxed as a substrate at low concentrations and acts as an inhibitor at high concentrations. Our direct observations revealed that low concentrations induced active dynamics in P-gp, whereas high concentrations severely restricted its motion, leading to a rigid, non-productive state. Our study provides critical insights into how observing molecular motion itself can unravel complex biological mechanisms.
History
DepositionSep 1, 2025-
Header (metadata) releaseApr 8, 2026-
Map releaseApr 8, 2026-
UpdateApr 8, 2026-
Current statusApr 8, 2026Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_66043.png

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Map

FileDownload / File: emd_66043.map.gz / Format: CCP4 / Size: 3.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
2.25 Å/pix.
x 100 pix.
= 225. Å		2.25 Å/pix.
x 100 pix.
= 225. Å		2.25 Å/pix.
x 100 pix.
= 225. Å

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Images are generated by Spider.

Voxel sizeX=Y=Z: 2.25 Å
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Contour LevelBy AUTHOR: 0.411
Minimum - Maximum-0.48035327 - 1.4581434
Average (Standard dev.)0.007306922 (±0.11094714)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions100100100
Spacing100100100
CellA=B=C: 225.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_66043_msk_1.map
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Additional map: #1

Fileemd_66043_additional_1.map
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Half map: #1

Fileemd_66043_half_map_1.map
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Half map: #2

Fileemd_66043_half_map_2.map
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Sample components

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Entire : ABCB1

EntireName: ABCB1
Components
  • Organelle or cellular component: ABCB1

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Supramolecule #1: ABCB1

SupramoleculeName: ABCB1 / type: organelle_or_cellular_component / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human)

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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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k 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: 2.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 7.17 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 81908
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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