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- EMDB-22321: Cryo-EM structure of bedaquiline-saturated Mycobacterium smegmati... -

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Basic information

Entry
Database: EMDB / ID: EMD-22321
TitleCryo-EM structure of bedaquiline-saturated Mycobacterium smegmatis ATP synthase FO region
Map dataLocally sharpened map.
Sample
  • Complex: FO region of ATP synthase from Mycobacterium smegmatis
    • Protein or peptide: ATP synthase subunit a
    • Protein or peptide: ATP synthase subunit b
    • Protein or peptide: ATP synthase subunit b-delta
    • Protein or peptide: ATP synthase subunit c
  • Ligand: Bedaquiline
KeywordsBedaquiline / Sirturo / TMC207 / T207910 / ATP synthase / mycobacteria / tuberculosis / HYDROLASE
Function / homology
Function and homology information


: / proton motive force-driven plasma membrane ATP synthesis / proton-transporting two-sector ATPase complex, proton-transporting domain / proton-transporting ATPase activity, rotational mechanism / membrane => GO:0016020 / proton-transporting ATP synthase complex / proton-transporting ATP synthase activity, rotational mechanism / hydrolase activity / lipid binding / plasma membrane
Similarity search - Function
ATP synthase, F0 complex, subunit b, bacterial / F-type ATP synthase subunit B-like, membrane domain superfamily / : / ATP synthase, F0 complex, subunit A, bacterial/chloroplast / ATP synthase, F0 complex, subunit b/b', bacterial/chloroplast / ATP synthase B/B' CF(0) / ATP synthase, F0 complex, subunit C, bacterial/chloroplast / ATP synthase, F0 complex, subunit A / ATP synthase, F0 complex, subunit A, active site / ATP synthase, F0 complex, subunit A superfamily ...ATP synthase, F0 complex, subunit b, bacterial / F-type ATP synthase subunit B-like, membrane domain superfamily / : / ATP synthase, F0 complex, subunit A, bacterial/chloroplast / ATP synthase, F0 complex, subunit b/b', bacterial/chloroplast / ATP synthase B/B' CF(0) / ATP synthase, F0 complex, subunit C, bacterial/chloroplast / ATP synthase, F0 complex, subunit A / ATP synthase, F0 complex, subunit A, active site / ATP synthase, F0 complex, subunit A superfamily / ATP synthase A chain / ATP synthase a subunit signature. / ATPase, OSCP/delta subunit / ATP synthase delta (OSCP) subunit / ATP synthase, F0 complex, subunit C / F1F0 ATP synthase subunit C superfamily / ATP synthase, F0 complex, subunit C, DCCD-binding site / ATP synthase c subunit signature. / V-ATPase proteolipid subunit C-like domain / F/V-ATP synthase subunit C superfamily / ATP synthase subunit C
Similarity search - Domain/homology
ATP synthase subunit b / ATP synthase subunit b-delta / ATP synthase subunit b / ATP synthase subunit c / ATP synthase subunit a / ATP synthase subunit c
Similarity search - Component
Biological speciesMycolicibacterium smegmatis (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsGuo H / Courbon GM
Funding support Canada, 2 items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR)PJT162186 Canada
Canadian Institutes of Health Research (CIHR)PJT156261 Canada
Citation
Journal: Nature / Year: 2021
Title: Structure of mycobacterial ATP synthase bound to the tuberculosis drug bedaquiline.
Authors: Hui Guo / Gautier M Courbon / Stephanie A Bueler / Juntao Mai / Jun Liu / John L Rubinstein /
Abstract: Tuberculosis-the world's leading cause of death by infectious disease-is increasingly resistant to current first-line antibiotics. The bacterium Mycobacterium tuberculosis (which causes tuberculosis) ...Tuberculosis-the world's leading cause of death by infectious disease-is increasingly resistant to current first-line antibiotics. The bacterium Mycobacterium tuberculosis (which causes tuberculosis) can survive low-energy conditions, allowing infections to remain dormant and decreasing their susceptibility to many antibiotics. Bedaquiline was developed in 2005 from a lead compound identified in a phenotypic screen against Mycobacterium smegmatis. This drug can sterilize even latent M. tuberculosis infections and has become a cornerstone of treatment for multidrug-resistant and extensively drug-resistant tuberculosis. Bedaquiline targets the mycobacterial ATP synthase, which is an essential enzyme in the obligate aerobic Mycobacterium genus, but how it binds the intact enzyme is unknown. Here we determined cryo-electron microscopy structures of M. smegmatis ATP synthase alone and in complex with bedaquiline. The drug-free structure suggests that hook-like extensions from the α-subunits prevent the enzyme from running in reverse, inhibiting ATP hydrolysis and preserving energy in hypoxic conditions. Bedaquiline binding induces large conformational changes in the ATP synthase, creating tight binding pockets at the interface of subunits a and c that explain the potency of this drug as an antibiotic for tuberculosis.
#1: Journal: Biorxiv / Year: 2020
Title: Structure of mycobacterial ATP synthase with the TB drug bedaquiline
Authors: Guo H / Courbon GM / Bueler SA / Mai J / Liu J / Rubinstein JL
History
DepositionJul 18, 2020-
Header (metadata) releaseAug 19, 2020-
Map releaseAug 19, 2020-
UpdateMay 14, 2025-
Current statusMay 14, 2025Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 3.5
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 3.5
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7jgc
  • Surface level: 3.5
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_22321.png

Downloads & links

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Map

FileDownload / File: emd_22321.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationLocally sharpened map.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.03 Å/pix.
x 320 pix.
= 329.6 Å		1.03 Å/pix.
x 320 pix.
= 329.6 Å		1.03 Å/pix.
x 320 pix.
= 329.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.03 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 3.5 / Movie #1: 3.5
Minimum - Maximum-0.25363797 - 35.353065000000001
Average (Standard dev.)0.007052383 (±0.27243283)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 329.59998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.031.031.03
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z329.600329.600329.600
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-0.25435.3530.007

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Supplemental data

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Mask #1

Fileemd_22321_msk_1.map
Projections & Slices
AxesZYX

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Additional map: Unsharpened map.

Fileemd_22321_additional.map
AnnotationUnsharpened map.
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Unsharpened map.

Fileemd_22321_additional_1.map
AnnotationUnsharpened map.
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 1.

Fileemd_22321_half_map_1.map
AnnotationHalf map 1.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 2.

Fileemd_22321_half_map_2.map
AnnotationHalf map 2.
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AxesZYX

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Histogram (log scale)

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Sample components

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Entire : FO region of ATP synthase from Mycobacterium smegmatis

EntireName: FO region of ATP synthase from Mycobacterium smegmatis
Components
  • Complex: FO region of ATP synthase from Mycobacterium smegmatis
    • Protein or peptide: ATP synthase subunit a
    • Protein or peptide: ATP synthase subunit b
    • Protein or peptide: ATP synthase subunit b-delta
    • Protein or peptide: ATP synthase subunit c
  • Ligand: Bedaquiline

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Supramolecule #1: FO region of ATP synthase from Mycobacterium smegmatis

SupramoleculeName: FO region of ATP synthase from Mycobacterium smegmatis
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Mycolicibacterium smegmatis (bacteria)
Molecular weightTheoretical: 110 KDa

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Macromolecule #1: ATP synthase subunit a

MacromoleculeName: ATP synthase subunit a / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mycolicibacterium smegmatis (bacteria)
Molecular weightTheoretical: 27.568482 KDa
SequenceString: MLAAEEGGAA IHVGHHTLVF ELFGMTFNGD TILATAVTAV IVIALAFYLR AKVTSTGVPS GVQLFWEALT IQMRQQIEGS IGMKIAPFV LPLSVTIFVF ILISNWLAVL PLQYGGADGA AAELYKAPAS DINFVLALAL FVFVCYHAAG IWRRGIVGHP I KVVKGHVA ...String:
MLAAEEGGAA IHVGHHTLVF ELFGMTFNGD TILATAVTAV IVIALAFYLR AKVTSTGVPS GVQLFWEALT IQMRQQIEGS IGMKIAPFV LPLSVTIFVF ILISNWLAVL PLQYGGADGA AAELYKAPAS DINFVLALAL FVFVCYHAAG IWRRGIVGHP I KVVKGHVA FLAPINIVEE LAKPISLALR LFGNIFAGGI LVALIAMFPW YIQWFPNAVW KTFDLFVGLI QAFIFSLLTI LY FSQSMEL DHEDH

UniProtKB: ATP synthase subunit a

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Macromolecule #2: ATP synthase subunit b

MacromoleculeName: ATP synthase subunit b / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mycolicibacterium smegmatis (bacteria)
Molecular weightTheoretical: 17.636701 KDa
SequenceString:
MGEFSATILA ASQAAEEGGG GSNFLIPNGT FFAVLIIFLI VLGVISKWVV PPISKVLAER EAMLAKTAAD NRKSAEQVAA AQADYEKEM AEARAQASAL RDEARAAGRS VVDEKRAQAS GEVAQTLTQA DQQLSAQGDQ VRSGLESSVD GLSAKLASRI L GVDVNSGG TQ

UniProtKB: ATP synthase subunit b

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Macromolecule #3: ATP synthase subunit b-delta

MacromoleculeName: ATP synthase subunit b-delta / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mycolicibacterium smegmatis (bacteria)
Molecular weightTheoretical: 47.504723 KDa
SequenceString: MSIFIGQLIG FAVIAFIIVK WVVPPVRTLM RNQQEAVRAA LAESAEAAKK LADADAMHAK ALADAKAESE KVTEEAKQDS ERIAAQLSE QAGSEAERIK AQGAQQIQLM RQQLIRQLRT GLGAEAVNKA AEIVRAHVAD PQAQSATVDR FLSELEQMAP S SVVIDTAA ...String:
MSIFIGQLIG FAVIAFIIVK WVVPPVRTLM RNQQEAVRAA LAESAEAAKK LADADAMHAK ALADAKAESE KVTEEAKQDS ERIAAQLSE QAGSEAERIK AQGAQQIQLM RQQLIRQLRT GLGAEAVNKA AEIVRAHVAD PQAQSATVDR FLSELEQMAP S SVVIDTAA TSRLRAASRQ SLAALVEKFD SVAGGLDADG LTNLADELAS VAKLLLSETA LNKHLAEPTD DSAPKVRLLE RL LSDKVSA TTLDLLRTAV SNRWSTESNL IDAVEHTARL ALLKRAEIAG EVDEVEEQLF RFGRVLDAEP RLSALLSDYT TPA EGRVAL LDKALTGRPG VNQTAAALLS QTVGLLRGER ADEAVIDLAE LAVSRRGEVV AHVSAAAELS DAQRTRLTEV LSRI YGRPV SVQLHVDPEL LGGLSITVGD EVIDGSIASR LAAAQTGLPD

UniProtKB: ATP synthase subunit b-delta

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Macromolecule #4: ATP synthase subunit c

MacromoleculeName: ATP synthase subunit c / type: protein_or_peptide / ID: 4 / Number of copies: 9 / Enantiomer: LEVO
Source (natural)Organism: Mycolicibacterium smegmatis (bacteria)
Molecular weightTheoretical: 8.597982 KDa
SequenceString:
MDLDPNAIIT AGALIGGGLI MGGGAIGAGI GDGIAGNALI SGIARQPEAQ GRLFTPFFIT VGLVEAAYFI NLAFMALFVF ATPGLQ

UniProtKB: ATP synthase subunit c

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Macromolecule #5: Bedaquiline

MacromoleculeName: Bedaquiline / type: ligand / ID: 5 / Number of copies: 7 / Formula: BQ1
Molecular weightTheoretical: 555.505 Da
Chemical component information

ChemComp-BQ1:
Bedaquiline / antibiotic*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

Concentration6 mg/mL
BufferpH: 7.4
GridModel: Homemade / Material: COPPER/RHODIUM / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 120 sec. / Pretreatment - Atmosphere: OTHER
VitrificationCryogen name: ETHANE-PROPANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK III

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number real images: 7589 / Average electron dose: 41.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Calibrated defocus max: 3.0 µm / Calibrated defocus min: 0.6 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal magnification: 75000
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: 1825672
CTF correctionSoftware - Name: cryoSPARC (ver. 2.13) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: BACK PROJECTION / Resolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2.13) / Number images used: 155488
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: cryoSPARC (ver. 2.13)
Final angle assignmentType: PROJECTION MATCHING / Software - Name: cryoSPARC (ver. 2.13)
Final 3D classificationNumber classes: 3 / Avg.num./class: 265978 / Software - Name: cryoSPARC (ver. 2.13)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: RECIPROCAL / Protocol: AB INITIO MODEL
Output model

PDB-7jgc:
Cryo-EM structure of bedaquiline-saturated Mycobacterium smegmatis ATP synthase FO region

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