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- EMDB-42205: Multidrug efflux pump EfpA from mycobacterium smegmatis -

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Basic information

Entry
Database: EMDB / ID: EMD-42205
TitleMultidrug efflux pump EfpA from mycobacterium smegmatis
Map data
Sample
  • Organelle or cellular component: multidrug efflux pump MsEfpA
    • Protein or peptide: Integral membrane efflux protein EfpA
  • Ligand: PHOSPHATIDYLETHANOLAMINE
Keywordsmultidrug efflux pump / EfpA / Mycobacterium smegmatis / 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 / Putative MFS-type transporter EfpA
Function and homology information
Biological speciesMycolicibacterium smegmatis (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.68 Å
AuthorsWang S / Liao M
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) 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 4, 2023-
Header (metadata) releaseSep 11, 2024-
Map releaseSep 11, 2024-
UpdateSep 11, 2024-
Current statusSep 11, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_42205.png

Downloads & links

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Map

FileDownload / File: emd_42205.map.gz / Format: CCP4 / Size: 16.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 164 pix.
= 180.4 Å		1.1 Å/pix.
x 164 pix.
= 180.4 Å		1.1 Å/pix.
x 164 pix.
= 180.4 Å

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.865
Minimum - Maximum-3.511653 - 4.3771095
Average (Standard dev.)0.0028274741 (±0.14413613)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions164164164
Spacing164164164
CellA=B=C: 180.40001 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_42205_msk_1.map
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Half map: #1

Fileemd_42205_half_map_1.map
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Half map: #2

Fileemd_42205_half_map_2.map
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Sample components

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Entire : multidrug efflux pump MsEfpA

EntireName: multidrug efflux pump MsEfpA
Components
  • Organelle or cellular component: multidrug efflux pump MsEfpA
    • Protein or peptide: Integral membrane efflux protein EfpA
  • Ligand: PHOSPHATIDYLETHANOLAMINE

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Supramolecule #1: multidrug efflux pump MsEfpA

SupramoleculeName: multidrug efflux pump MsEfpA / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mycolicibacterium smegmatis (bacteria)

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Macromolecule #1: Integral membrane efflux protein EfpA

MacromoleculeName: Integral membrane efflux protein EfpA / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mycolicibacterium smegmatis (bacteria)
Molecular weightTheoretical: 48.39991 KDa
Recombinant expressionOrganism: Mycolicibacterium smegmatis (bacteria)
SequenceString: WGFLSAVIAI GGMQLLATMD STVAIVALPK IQDELSLSDA GRSWVITAYV LTFGGLMLLG GRLGDTIGRK RTFIVGVMLF TIASVLCGI AWNETTLVTA RLLQGVGAAI ASPTGLALVA TTFPKGPARN AATAVFGAMT AIGSVMGLVV GGALTEVSWR W AFLVNVPI ...String:
WGFLSAVIAI GGMQLLATMD STVAIVALPK IQDELSLSDA GRSWVITAYV LTFGGLMLLG GRLGDTIGRK RTFIVGVMLF TIASVLCGI AWNETTLVTA RLLQGVGAAI ASPTGLALVA TTFPKGPARN AATAVFGAMT AIGSVMGLVV GGALTEVSWR W AFLVNVPI GLVMVYLART ALQETNRERM KLDAAGALLA TLACTAAVFA FTQGPESGWL APITLASGAA ALVFGLAFLI AE RNAENPV VPFALFRERN RVATFAAIFL AGGVLFTLTV LIGLYVQDIL GYSALRAGVG FIPFVIGMGI GLGAASQLVR SIP PRVLVI AGGILVLGAM IYGSTLHRGI PYFPNLVLPI TIGGIGIGTI VVPLTLSAIA GVNLDRIGPA SAIALMLQNL GGPL VLAVI QAVITSRTLF LGGTTGPVKA MNDEQIGALD AAYTYGLLWV AAVAVLVGAA ALFIGYTSQQ VAHAQ

UniProtKB: Putative MFS-type transporter EfpA

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Macromolecule #2: PHOSPHATIDYLETHANOLAMINE

MacromoleculeName: PHOSPHATIDYLETHANOLAMINE / type: ligand / ID: 2 / Number of copies: 1 / Formula: PTY
Molecular weightTheoretical: 734.039 Da
Chemical component information

ChemComp-PTY:
PHOSPHATIDYLETHANOLAMINE / phospholipid*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation state2D array

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Sample preparation

BufferpH: 8
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: BRIGHT FIELD / 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: 3.68 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 52150
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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