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- EMDB-42204: Multidrug efflux pump MtEfpA bound with inhibitor BRD8000.3 -

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Basic information

Entry
Database: EMDB / ID: EMD-42204
TitleMultidrug efflux pump MtEfpA bound with inhibitor BRD8000.3
Map data
Sample
  • Organelle or cellular component: Complex of Multidrug efflux pump MtEfpA with lipids and inhibitor BRD8000.3
    • Protein or peptide: Integral membrane efflux protein EFPA
  • Ligand: PHOSPHATIDYLETHANOLAMINE
  • Ligand: (1S,3S)-N-[6-bromo-5-(pyrimidin-2-yl)pyridin-2-yl]-2,2-dimethyl-3-(2-methylpropyl)cyclopropane-1-carboxamide
Keywordsmultidrug efflux pump / EfpA / mycobacterium / BRD8000.3 / TRANSPORT PROTEIN
Function / homologyMajor facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / transmembrane transporter activity / MFS transporter superfamily / plasma membrane / MFS-type transporter EfpA
Function and homology information
Biological speciesMycobacterium tuberculosis (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.26 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_42204.png

Downloads & links

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Map

FileDownload / File: emd_42204.map.gz / Format: CCP4 / Size: 125 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.)
0.79 Å/pix.
x 320 pix.
= 252.16 Å		0.79 Å/pix.
x 320 pix.
= 252.16 Å		0.79 Å/pix.
x 320 pix.
= 252.16 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.788 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.328
Minimum - Maximum-1.3486392 - 2.380884
Average (Standard dev.)-0.0003981459 (±0.05463562)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 252.16 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_42204_half_map_1.map
Projections & Slices
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Half map: #2

Fileemd_42204_half_map_2.map
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Sample components

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Entire : Complex of Multidrug efflux pump MtEfpA with lipids and inhibitor...

EntireName: Complex of Multidrug efflux pump MtEfpA with lipids and inhibitor BRD8000.3
Components
  • Organelle or cellular component: Complex of Multidrug efflux pump MtEfpA with lipids and inhibitor BRD8000.3
    • Protein or peptide: Integral membrane efflux protein EFPA
  • Ligand: PHOSPHATIDYLETHANOLAMINE
  • Ligand: (1S,3S)-N-[6-bromo-5-(pyrimidin-2-yl)pyridin-2-yl]-2,2-dimethyl-3-(2-methylpropyl)cyclopropane-1-carboxamide

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Supramolecule #1: Complex of Multidrug efflux pump MtEfpA with lipids and inhibitor...

SupramoleculeName: Complex of Multidrug efflux pump MtEfpA with lipids and inhibitor BRD8000.3
type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mycobacterium tuberculosis (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: 2 / Enantiomer: LEVO
Source (natural)Organism: Mycobacterium tuberculosis (bacteria)
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: 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: (1S,3S)-N-[6-bromo-5-(pyrimidin-2-yl)pyridin-2-yl]-2,2-dimethyl-3...

MacromoleculeName: (1S,3S)-N-[6-bromo-5-(pyrimidin-2-yl)pyridin-2-yl]-2,2-dimethyl-3-(2-methylpropyl)cyclopropane-1-carboxamide
type: ligand / ID: 3 / Number of copies: 2 / Formula: WJI
Molecular weightTheoretical: 403.316 Da

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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 TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (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: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.26 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 52099
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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