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- EMDB-51371: Truncated MmpL4 mutant R375E/R383E. -

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Basic information

Entry
Database: EMDB / ID: EMD-51371
TitleTruncated MmpL4 mutant R375E/R383E.
Map dataTruncated MmpL4 R375E/R383E mutant in detergent at a resolution of 5.1A.
Sample
  • Complex: Truncated MmpL4 R375E/R383E.
KeywordsRND superfamily MmpL family Siderophore export Drug resistance Acyl carrier protein / MEMBRANE PROTEIN
Biological speciesMycobacterium tuberculosis (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.1 Å
AuthorsEarp JC / Garaeva AA / Seeger MA
Funding supportEuropean Union, Switzerland, United States, 4 items
OrganizationGrant numberCountry
European Research Council (ERC)772190European Union
University of ZurichFK-21-041 Switzerland
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R21 AI151239 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01 AI137338 United States
CitationJournal: Nat Commun / Year: 2025
Title: Structural basis of siderophore export and drug efflux by Mycobacterium tuberculosis.
Authors: Jennifer C Earp / Alisa A Garaeva / Virginia Meikle / Michael Niederweis / Markus A Seeger /
Abstract: To replicate and cause disease, Mycobacterium tuberculosis secretes siderophores called mycobactins to scavenge iron from the human host. Two closely related transporters, MmpL4 and MmpL5, are ...To replicate and cause disease, Mycobacterium tuberculosis secretes siderophores called mycobactins to scavenge iron from the human host. Two closely related transporters, MmpL4 and MmpL5, are required for mycobactin secretion and drug efflux. In clinical strains, overproduction of MmpL5 confers resistance towards bedaquiline and clofazimine, key drugs to combat multidrug resistant tuberculosis. Here, we present cryogenic-electron microscopy structures of MmpL4 and identify a mycobactin binding site, which is accessible from the cytosol and also required for bedaquiline efflux. An unusual coiled-coil domain predicted to extend 130 Å into the periplasm is essential for mycobactin and bedaquiline efflux by MmpL4 and MmpL5. The mycobacterial acyl carrier protein MbtL forms a complex with MmpL4, indicating that mycobactin synthesis and export are coupled. Thus, MmpL4 and MmpL5 constitute the core components of a unique multi-subunit machinery required for iron acquisition and drug efflux by M. tuberculosis.
History
DepositionAug 16, 2024-
Header (metadata) releaseFeb 19, 2025-
Map releaseFeb 19, 2025-
UpdateMar 5, 2025-
Current statusMar 5, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_51371.png

Downloads & links

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Map

FileDownload / File: emd_51371.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationTruncated MmpL4 R375E/R383E mutant in detergent at a resolution of 5.1A.
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.3 Å/pix.
x 200 pix.
= 260. Å		1.3 Å/pix.
x 200 pix.
= 260. Å		1.3 Å/pix.
x 200 pix.
= 260. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.3 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.171
Minimum - Maximum-0.3738286 - 0.6362917
Average (Standard dev.)0.0006618175 (±0.019803029)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 260.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_51371_msk_1.map
Projections & Slices
AxesZYX

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Histogram

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Half map: half-map 1 used for post processing step and...

Fileemd_51371_half_map_1.map
Annotationhalf-map 1 used for post processing step and FSC resolution calculation
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half-map 2 used for post processing step and...

Fileemd_51371_half_map_2.map
Annotationhalf-map 2 used for post processing step and FSC resolution calculation
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Truncated MmpL4 R375E/R383E.

EntireName: Truncated MmpL4 R375E/R383E.
Components
  • Complex: Truncated MmpL4 R375E/R383E.

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Supramolecule #1: Truncated MmpL4 R375E/R383E.

SupramoleculeName: Truncated MmpL4 R375E/R383E. / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Mycobacterium tuberculosis (bacteria)
Molecular weightTheoretical: 105 KDa

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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

Concentration9 mg/mL
BufferpH: 7.5 / Details: 20mM Tris-HCl pH 7.5, 150mM NaCl, 0.03% DDM
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 39.0 kPa / Details: at 15 mA
VitrificationCryogen name: ETHANE-PROPANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Digitization - Dimensions - Width: 5760 pixel / Digitization - Dimensions - Height: 4092 pixel / Number grids imaged: 1 / Number real images: 3233 / Average exposure time: 1.3 sec. / Average electron dose: 63.3 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Calibrated defocus max: 2.2 µm / Calibrated defocus min: 1.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 130000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1128145
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 5.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. v4.1.2) / Number images used: 68098
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.1.2)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. v4.1.2)
FSC plot (resolution estimation)

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