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- EMDB-37641: multidrug transporter EfpA from Mycobacterium tuberculosis bound ... -

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Basic information

Entry
Database: EMDB / ID: EMD-37641
Titlemultidrug transporter EfpA from Mycobacterium tuberculosis bound with lipids
Map data
Sample
  • Complex: complex of multidrug efflux pump EfpA with lipids
    • Protein or peptide: Efflux pump A
  • Ligand: PHOSPHATIDYLETHANOLAMINE
  • Ligand: CARDIOLIPIN
Keywordsmultidrug transporter / EfpA / mycobacterium / lipid / TRANSPORT PROTEIN
Function / homologyMajor facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / transmembrane transporter activity / MFS transporter superfamily / membrane / plasma membrane / Uncharacterized MFS-type transporter EfpA
Function and homology information
Biological speciesMycobacterium tuberculosis H37Rv (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.04 Å
AuthorsWang S / Liao M
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: Nat Commun / Year: 2024
Title: Structures of the Mycobacterium tuberculosis efflux pump EfpA reveal the mechanisms of transport and inhibition.
Authors: Shuhui Wang / Kun Wang / Kangkang Song / Zon Weng Lai / Pengfei Li / Dongying Li / Yajie Sun / Ye Mei / Chen Xu / Maofu Liao /
Abstract: As the first identified multidrug efflux pump in Mycobacterium tuberculosis (Mtb), EfpA is an essential protein and promising drug target. However, the functional and inhibitory mechanisms of EfpA ...As the first identified multidrug efflux pump in Mycobacterium tuberculosis (Mtb), EfpA is an essential protein and promising drug target. However, the functional and inhibitory mechanisms of EfpA are poorly understood. Here we report cryo-EM structures of EfpA in outward-open conformation, either bound to three endogenous lipids or the inhibitor BRD-8000.3. Three lipids inside EfpA span from the inner leaflet to the outer leaflet of the membrane. BRD-8000.3 occupies one lipid site at the level of inner membrane leaflet, competitively inhibiting lipid binding. EfpA resembles the related lysophospholipid transporter MFSD2A in both overall structure and lipid binding sites and may function as a lipid flippase. Combining AlphaFold-predicted EfpA structure, which is inward-open, we propose a complete conformational transition cycle for EfpA. Together, our results provide a structural and mechanistic foundation to comprehend EfpA function and develop EfpA-targeting anti-TB drugs.
History
DepositionOct 3, 2023-
Header (metadata) releaseSep 11, 2024-
Map releaseSep 11, 2024-
UpdateSep 18, 2024-
Current statusSep 18, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_37641.png

Downloads & links

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Map

FileDownload / File: emd_37641.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.87 Å/pix.
x 320 pix.
= 278.4 Å		0.87 Å/pix.
x 320 pix.
= 278.4 Å		0.87 Å/pix.
x 320 pix.
= 278.4 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.87 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.827
Minimum - Maximum-2.7084706 - 4.4842453
Average (Standard dev.)-0.0012719884 (±0.105866164)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 278.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_37641_msk_1.map
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Half map: #1

Fileemd_37641_half_map_1.map
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Half map: #2

Fileemd_37641_half_map_2.map
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Sample components

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Entire : complex of multidrug efflux pump EfpA with lipids

EntireName: complex of multidrug efflux pump EfpA with lipids
Components
  • Complex: complex of multidrug efflux pump EfpA with lipids
    • Protein or peptide: Efflux pump A
  • Ligand: PHOSPHATIDYLETHANOLAMINE
  • Ligand: CARDIOLIPIN

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Supramolecule #1: complex of multidrug efflux pump EfpA with lipids

SupramoleculeName: complex of multidrug efflux pump EfpA with lipids / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mycobacterium tuberculosis H37Rv (bacteria)
Molecular weightTheoretical: 110 KDa

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Macromolecule #1: Efflux pump A

MacromoleculeName: Efflux pump A / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mycobacterium tuberculosis H37Rv (bacteria) / Strain: H37Rv
Molecular weightTheoretical: 55.620098 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MTALNDTERA VRNWTAGRPH RPAPMRPPRS EETASERPSR YYPTWLPSRS FIAAVIAIGG MQLLATMDST VAIVALPKIQ NELSLSDAG RSWVITAYVL TFGGLMLLGG RLGDTIGRKR TFIVGVALFT ISSVLCAVAW DEATLVIARL SQGVGSAIAS P TGLALVAT ...String:
MTALNDTERA VRNWTAGRPH RPAPMRPPRS EETASERPSR YYPTWLPSRS FIAAVIAIGG MQLLATMDST VAIVALPKIQ NELSLSDAG RSWVITAYVL TFGGLMLLGG RLGDTIGRKR TFIVGVALFT ISSVLCAVAW DEATLVIARL SQGVGSAIAS P TGLALVAT TFPKGPARNA ATAVFAAMTA IGSVMGLVVG GALTEVSWRW AFLVNVPIGL VMIYLARTAL RETNKERMKL DA TGAILAT LACTAAVFAF SIGPEKGWMS GITIGSGLVA LAAAVAFVIV ERTAENPVVP FHLFRDRNRL VTFSAILLAG GVM FSLTVC IGLYVQDILG YSALRAGVGF IPFVIAMGIG LGVSSQLVSR FSPRVLTIGG GYLLFGAMLY GSFFMHRGVP YFPN LVMPI VVGGIGIGMA VVPLTLSAIA GVGFDQIGPV SAIALMLQSL GGPLVLAVIQ AVITSRTLYL GGTTGPVKFM NDVQL AALD HAYTYGLLWV AGAAIIVGGM ALFIGYTPQQ VAHAQEVKEA IDAGEL

UniProtKB: Uncharacterized MFS-type transporter EfpA

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Macromolecule #2: PHOSPHATIDYLETHANOLAMINE

MacromoleculeName: PHOSPHATIDYLETHANOLAMINE / type: ligand / ID: 2 / Number of copies: 4 / Formula: PTY
Molecular weightTheoretical: 734.039 Da
Chemical component information

ChemComp-PTY:
PHOSPHATIDYLETHANOLAMINE / phospholipid*YM

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Macromolecule #3: CARDIOLIPIN

MacromoleculeName: CARDIOLIPIN / type: ligand / ID: 3 / Number of copies: 1 / Formula: CDL
Molecular weightTheoretical: 1.464043 KDa
Chemical component information

ChemComp-CDL:
CARDIOLIPIN / phospholipid*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: 8
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY ARRAY
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: OTHER / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.04 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 49783
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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