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- EMDB-21894: Monomer yeast ATP synthase Fo reconstituted in nanodisc with inhi... -

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Basic information

Entry
Database: EMDB / ID: EMD-21894
TitleMonomer yeast ATP synthase Fo reconstituted in nanodisc with inhibitor of Bedaquiline bound
Map dataMonomer yeast ATP synthase Fo reconstituted in nanodisc in the presence of Bedaquiline
Sample
  • Complex: Monomer yeast ATP synthase Fo reconstituted in nanodisc generated in the presence of Bedaquiline
    • Protein or peptide: ATP synthase subunit 9, mitochondrial
    • Protein or peptide: ATP synthase protein 8
    • Protein or peptide: ATP synthase subunit a
    • Protein or peptide: ATP synthase subunit 4, mitochondrial
    • Protein or peptide: ATP synthase subunit d, mitochondrial
    • Protein or peptide: ATP synthase subunit f, mitochondrial
    • Protein or peptide: ATP synthase subunit J, mitochondrial
KeywordsATP synthase / BIOSYNTHETIC PROTEIN
Function / homology
Function and homology information


: / Mitochondrial protein degradation / mitochondrial proton-transporting ATP synthase complex assembly / proton-transporting ATP synthase complex / proton transmembrane transporter activity / proton motive force-driven ATP synthesis / : / proton transmembrane transport / mitochondrial intermembrane space / protein-containing complex assembly ...: / Mitochondrial protein degradation / mitochondrial proton-transporting ATP synthase complex assembly / proton-transporting ATP synthase complex / proton transmembrane transporter activity / proton motive force-driven ATP synthesis / : / proton transmembrane transport / mitochondrial intermembrane space / protein-containing complex assembly / mitochondrial inner membrane / lipid binding / mitochondrion / identical protein binding / cytosol
Similarity search - Function
ATP synthase, F0 complex, subunit J / ATP synthase protein 8, fungal type / ATP synthase, F0 complex, subunit F, mitochondria, fungi / ATP synthase j chain / Fungal ATP synthase protein 8 (A6L) / Mitochondrial F1-F0 ATP synthase subunit F of fungi / ATP synthase, F0 complex, subunit B/MI25 / ATP synthase, F0 complex, subunit B / Mitochondrial ATP synthase B chain precursor (ATP-synt_B) / ATP synthase, F0 complex, subunit D, mitochondrial ...ATP synthase, F0 complex, subunit J / ATP synthase protein 8, fungal type / ATP synthase, F0 complex, subunit F, mitochondria, fungi / ATP synthase j chain / Fungal ATP synthase protein 8 (A6L) / Mitochondrial F1-F0 ATP synthase subunit F of fungi / ATP synthase, F0 complex, subunit B/MI25 / ATP synthase, F0 complex, subunit B / Mitochondrial ATP synthase B chain precursor (ATP-synt_B) / ATP synthase, F0 complex, subunit D, mitochondrial / ATP synthase D chain, mitochondrial (ATP5H) / ATP synthase, F0 complex, subunit D superfamily, mitochondrial / ATP synthase, F0 complex, subunit A, bacterial/mitochondria / 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. / 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 a / ATP synthase protein 8 / ATP synthase subunit 4, mitochondrial / ATP synthase subunit d, mitochondrial / ATP synthase subunit 9, mitochondrial / ATP synthase subunit J, mitochondrial / ATP synthase subunit f, mitochondrial
Similarity search - Component
Biological speciesSaccharomyces cerevisiae (brewer's yeast) / Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (yeast)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.2 Å
AuthorsMueller DM / Srivastava AP
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Library of Medicine (NIH/NLM)R01GM66223 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM131731 United States
CitationJournal: Commun Biol / Year: 2020
Title: Bedaquiline inhibits the yeast and human mitochondrial ATP synthases.
Authors: Min Luo / Wenchang Zhou / Hiral Patel / Anurag P Srivastava / Jindrich Symersky / Michał M Bonar / José D Faraldo-Gómez / Maofu Liao / David M Mueller /
Abstract: Bedaquiline (BDQ, Sirturo) has been approved to treat multidrug resistant forms of Mycobacterium tuberculosis. Prior studies suggested that BDQ was a selective inhibitor of the ATP synthase from M. ...Bedaquiline (BDQ, Sirturo) has been approved to treat multidrug resistant forms of Mycobacterium tuberculosis. Prior studies suggested that BDQ was a selective inhibitor of the ATP synthase from M. tuberculosis. However, Sirturo treatment leads to an increased risk of cardiac arrhythmias and death, raising the concern that this adverse effect results from inhibition at a secondary site. Here we show that BDQ is a potent inhibitor of the yeast and human mitochondrial ATP synthases. Single-particle cryo-EM reveals that the site of BDQ inhibition partially overlaps with that of the inhibitor oligomycin. Molecular dynamics simulations indicate that the binding mode of BDQ to this site is similar to that previously seen for a mycobacterial enzyme, explaining the observed lack of selectivity. We propose that derivatives of BDQ ought to be made to increase its specificity toward the mycobacterial enzyme and thereby reduce the side effects for patients that are treated with Sirturo.
History
DepositionMay 2, 2020-
Header (metadata) releaseAug 26, 2020-
Map releaseAug 26, 2020-
UpdateNov 20, 2024-
Current statusNov 20, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.043
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.043
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6wtd
  • Surface level: 0.043
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6wtd
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21894.png

Downloads & links

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Map

FileDownload / File: emd_21894.map.gz / Format: CCP4 / Size: 27 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMonomer yeast ATP synthase Fo reconstituted in nanodisc in the presence of Bedaquiline
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.24 Å/pix.
x 192 pix.
= 238.08 Å		1.24 Å/pix.
x 192 pix.
= 238.08 Å		1.24 Å/pix.
x 192 pix.
= 238.08 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.24 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.043 / Movie #1: 0.043
Minimum - Maximum-0.18169104 - 0.23413275
Average (Standard dev.)0.0008823943 (±0.01025757)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions192192192
Spacing192192192
CellA=B=C: 238.08 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.241.241.24
M x/y/z192192192
origin x/y/z0.0000.0000.000
length x/y/z238.080238.080238.080
α/β/γ90.00090.00090.000
start NX/NY/NZ-64-64-64
NX/NY/NZ128128128
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS192192192
D min/max/mean-0.1820.2340.001

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Supplemental data

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Sample components

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Entire : Monomer yeast ATP synthase Fo reconstituted in nanodisc generated...

EntireName: Monomer yeast ATP synthase Fo reconstituted in nanodisc generated in the presence of Bedaquiline
Components
  • Complex: Monomer yeast ATP synthase Fo reconstituted in nanodisc generated in the presence of Bedaquiline
    • Protein or peptide: ATP synthase subunit 9, mitochondrial
    • Protein or peptide: ATP synthase protein 8
    • Protein or peptide: ATP synthase subunit a
    • Protein or peptide: ATP synthase subunit 4, mitochondrial
    • Protein or peptide: ATP synthase subunit d, mitochondrial
    • Protein or peptide: ATP synthase subunit f, mitochondrial
    • Protein or peptide: ATP synthase subunit J, mitochondrial

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Supramolecule #1: Monomer yeast ATP synthase Fo reconstituted in nanodisc generated...

SupramoleculeName: Monomer yeast ATP synthase Fo reconstituted in nanodisc generated in the presence of Bedaquiline
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Saccharomyces cerevisiae (brewer's yeast) / Strain: ATCC 204508 / S288c

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Macromolecule #1: ATP synthase subunit 9, mitochondrial

MacromoleculeName: ATP synthase subunit 9, mitochondrial / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO
Source (natural)Organism: Saccharomyces cerevisiae (brewer's yeast)
Molecular weightTheoretical: 7.790385 KDa
SequenceString:
(FME)QLVLAAKYI GAGISTIGLL GAGIGIAIVF AALINGVSRN PSIKDTVFPM AILGFALSEA TGLFCLMVSF LLLFGV

UniProtKB: ATP synthase subunit 9, mitochondrial

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Macromolecule #2: ATP synthase protein 8

MacromoleculeName: ATP synthase protein 8 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Saccharomyces cerevisiae (brewer's yeast)
Molecular weightTheoretical: 5.825215 KDa
SequenceString:
MPQLVPFYFM NQLTYGFLLM ITLLILFSQF FLPMILRLYV SRLFISKL

UniProtKB: ATP synthase protein 8

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Macromolecule #3: ATP synthase subunit a

MacromoleculeName: ATP synthase subunit a / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Saccharomyces cerevisiae (brewer's yeast)
Molecular weightTheoretical: 27.90043 KDa
SequenceString: SPLDQFEIRT LFGLQSSFID LSCLNLTTFS LYTIIVLLVI TSLYTLTNNN NKIIGSRWLI SQEAIYDTIM NMTKGQIGGK NWGLYFPMI FTLFMFIFIA NLISMIPYSF ALSAHLVFII SLSIVIWLGN TILGLYKHGW VFFSLFVPAG TPLPLVPLLV I IETLSYFA ...String:
SPLDQFEIRT LFGLQSSFID LSCLNLTTFS LYTIIVLLVI TSLYTLTNNN NKIIGSRWLI SQEAIYDTIM NMTKGQIGGK NWGLYFPMI FTLFMFIFIA NLISMIPYSF ALSAHLVFII SLSIVIWLGN TILGLYKHGW VFFSLFVPAG TPLPLVPLLV I IETLSYFA RAISLGLRLG SNILAGHLLM VILAGLTFNF MLINLFTLVF GFVPLAMILA IMMLEFAIGI IQGYVWAILT AS YLKDAVY LH

UniProtKB: ATP synthase subunit a

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Macromolecule #4: ATP synthase subunit 4, mitochondrial

MacromoleculeName: ATP synthase subunit 4, mitochondrial / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (yeast)
Strain: ATCC 204508 / S288c
Molecular weightTheoretical: 23.194498 KDa
SequenceString: MSSTPEKQTD PKAKANSIIN AIPGNNILTK TGVLGTSAAA VIYAISNELY VINDESILLL TFLGFTGLVA KYLAPAYKDF ADARMKKVS DVLNASRNKH VEAVKDRIDS VSQLQNVAET TKVLFDVSKE TVELESEAFE LKQKVELAHE AKAVLDSWVR Y EASLRQLE ...String:
MSSTPEKQTD PKAKANSIIN AIPGNNILTK TGVLGTSAAA VIYAISNELY VINDESILLL TFLGFTGLVA KYLAPAYKDF ADARMKKVS DVLNASRNKH VEAVKDRIDS VSQLQNVAET TKVLFDVSKE TVELESEAFE LKQKVELAHE AKAVLDSWVR Y EASLRQLE QRQLAKSVIS RVQSELGNPK FQEKVLQQSI SEIEQLLSKL K

UniProtKB: ATP synthase subunit 4, mitochondrial

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Macromolecule #5: ATP synthase subunit d, mitochondrial

MacromoleculeName: ATP synthase subunit d, mitochondrial / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (yeast)
Strain: ATCC 204508 / S288c
Molecular weightTheoretical: 19.709424 KDa
SequenceString:
SLAKSAANKL DWAKVISSLR ITGSTATQLS SFKKRNDEAR RQLLELQSQP TEVDFSHYRS VLKNTSVIDK IESYVKQYKP VKIDASKQL QVIESFEKHA MTNAKETESL VSKELKDLQS TLDNIQSARP FDELTVDDLT KIKPEIDAKV EEMVKKGKWD V PGYKDRFG NLNVM

UniProtKB: ATP synthase subunit d, mitochondrial

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Macromolecule #6: ATP synthase subunit f, mitochondrial

MacromoleculeName: ATP synthase subunit f, mitochondrial / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (yeast)
Strain: ATCC 204508 / S288c
Molecular weightTheoretical: 10.584166 KDa
SequenceString:
VSTLIPPKVV SSKNIGSAPN AKRIANVVHF YKSLPQGPAP AIKANTRLAR YKAKYFDGDN ASGKPLWHFA LGIIAFGYSM EYYFHLRHH KGAEEH

UniProtKB: ATP synthase subunit f, mitochondrial

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Macromolecule #7: ATP synthase subunit J, mitochondrial

MacromoleculeName: ATP synthase subunit J, mitochondrial / type: protein_or_peptide / ID: 7 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (yeast)
Strain: ATCC 204508 / S288c
Molecular weightTheoretical: 4.145884 KDa
SequenceString:
MLKRFPTPIL KVYWPFFVAG AAVYYGMSKA ADLSSNT

UniProtKB: ATP synthase subunit J, mitochondrial

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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

Concentration1.5 mg/mL
BufferpH: 8 / Details: 20 mM Tris-HCl, 150 mM NaCl, pH 8.0
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 400 / Support film - Material: CARBON
VitrificationCryogen name: ETHANE / Chamber humidity: 91 %

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
TemperatureMin: 80.0 K / Max: 105.0 K
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number real images: 9258 / Average electron dose: 8.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsCalibrated defocus max: 2.8000000000000003 µm / Calibrated defocus min: 0.8 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.0 mm / Nominal magnification: 36000
Sample stageSpecimen holder model: GATAN LIQUID NITROGEN / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 541568
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Algorithm: BACK PROJECTION / Resolution.type: BY AUTHOR / Resolution: 4.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 2) / Number images used: 47169
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION (ver. 2)
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION (ver. 1.4)
Final 3D classificationNumber classes: 6 / Software - Name: RELION (ver. 1.4)

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Atomic model buiding 1

Initial modelPDB ID:

6cp7


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL
Output model

PDB-6wtd:
Monomer yeast ATP synthase Fo reconstituted in nanodisc with inhibitor of Bedaquiline bound

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