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Yorodumi- EMDB-21894: Monomer yeast ATP synthase Fo reconstituted in nanodisc with inhi... -
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-Basic information
Entry | Database: EMDB / ID: EMD-21894 | |||||||||
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Title | Monomer yeast ATP synthase Fo reconstituted in nanodisc with inhibitor of Bedaquiline bound | |||||||||
Map data | Monomer yeast ATP synthase Fo reconstituted in nanodisc in the presence of Bedaquiline | |||||||||
Sample |
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Function / homology | Function and homology information : / : / Mitochondrial protein degradation / mitochondrial proton-transporting ATP synthase complex assembly / : / : / : / proton motive force-driven ATP synthesis / proton transmembrane transporter activity / proton transmembrane transport ...: / : / Mitochondrial protein degradation / mitochondrial proton-transporting ATP synthase complex assembly / : / : / : / proton motive force-driven ATP synthesis / proton transmembrane transporter activity / proton transmembrane transport / mitochondrial intermembrane space / protein-containing complex assembly / mitochondrial inner membrane / lipid binding / mitochondrion / identical protein binding / cytosol Similarity search - Function | |||||||||
Biological species | Saccharomyces cerevisiae (brewer's yeast) / Baker's yeast (brewer's yeast) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 4.2 Å | |||||||||
Authors | Mueller DM / Srivastava AP / Symersky J / Luo M / Liao MF | |||||||||
Funding support | United States, 2 items
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Citation | Journal: 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 |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_21894.map.gz | 24.6 MB | EMDB map data format | |
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Header (meta data) | emd-21894-v30.xml emd-21894.xml | 18.5 KB 18.5 KB | Display Display | EMDB header |
Images | emd_21894.png | 115.4 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-21894 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-21894 | HTTPS FTP |
-Validation report
Summary document | emd_21894_validation.pdf.gz | 470.7 KB | Display | EMDB validaton report |
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Full document | emd_21894_full_validation.pdf.gz | 470.2 KB | Display | |
Data in XML | emd_21894_validation.xml.gz | 5.4 KB | Display | |
Data in CIF | emd_21894_validation.cif.gz | 6.2 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-21894 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-21894 | HTTPS FTP |
-Related structure data
Related structure data | 6wtdMC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_21894.map.gz / Format: CCP4 / Size: 27 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | Monomer yeast ATP synthase Fo reconstituted in nanodisc in the presence of Bedaquiline | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.24 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Sample components
-Entire : Monomer yeast ATP synthase Fo reconstituted in nanodisc generated...
Entire | Name: Monomer yeast ATP synthase Fo reconstituted in nanodisc generated in the presence of Bedaquiline |
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Components |
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-Supramolecule #1: Monomer yeast ATP synthase Fo reconstituted in nanodisc generated...
Supramolecule | Name: Monomer yeast ATP synthase Fo reconstituted in nanodisc generated in the presence of Bedaquiline type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Saccharomyces cerevisiae (brewer's yeast) / Strain: ATCC 204508 / S288c |
-Macromolecule #1: ATP synthase subunit 9, mitochondrial
Macromolecule | Name: ATP synthase subunit 9, mitochondrial / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO |
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Source (natural) | Organism: Baker's yeast (brewer's yeast) |
Molecular weight | Theoretical: 7.790385 KDa |
Sequence | String: (FME)QLVLAAKYI GAGISTIGLL GAGIGIAIVF AALINGVSRN PSIKDTVFPM AILGFALSEA TGLFCLMVSF LLLFGV |
-Macromolecule #2: ATP synthase protein 8
Macromolecule | Name: ATP synthase protein 8 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Baker's yeast (brewer's yeast) |
Molecular weight | Theoretical: 5.825215 KDa |
Sequence | String: MPQLVPFYFM NQLTYGFLLM ITLLILFSQF FLPMILRLYV SRLFISKL |
-Macromolecule #3: ATP synthase subunit a
Macromolecule | Name: ATP synthase subunit a / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Baker's yeast (brewer's yeast) |
Molecular weight | Theoretical: 27.90043 KDa |
Sequence | String: 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 |
-Macromolecule #4: ATP synthase subunit 4, mitochondrial
Macromolecule | Name: ATP synthase subunit 4, mitochondrial / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Baker's yeast (brewer's yeast) / Strain: ATCC 204508 / S288c |
Molecular weight | Theoretical: 23.194498 KDa |
Sequence | String: 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 |
-Macromolecule #5: ATP synthase subunit d, mitochondrial
Macromolecule | Name: ATP synthase subunit d, mitochondrial / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Baker's yeast (brewer's yeast) / Strain: ATCC 204508 / S288c |
Molecular weight | Theoretical: 19.709424 KDa |
Sequence | String: SLAKSAANKL DWAKVISSLR ITGSTATQLS SFKKRNDEAR RQLLELQSQP TEVDFSHYRS VLKNTSVIDK IESYVKQYKP VKIDASKQL QVIESFEKHA MTNAKETESL VSKELKDLQS TLDNIQSARP FDELTVDDLT KIKPEIDAKV EEMVKKGKWD V PGYKDRFG NLNVM |
-Macromolecule #6: ATP synthase subunit f, mitochondrial
Macromolecule | Name: ATP synthase subunit f, mitochondrial / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Baker's yeast (brewer's yeast) / Strain: ATCC 204508 / S288c |
Molecular weight | Theoretical: 10.584166 KDa |
Sequence | String: VSTLIPPKVV SSKNIGSAPN AKRIANVVHF YKSLPQGPAP AIKANTRLAR YKAKYFDGDN ASGKPLWHFA LGIIAFGYSM EYYFHLRHH KGAEEH |
-Macromolecule #7: ATP synthase subunit J, mitochondrial
Macromolecule | Name: ATP synthase subunit J, mitochondrial / type: protein_or_peptide / ID: 7 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Baker's yeast (brewer's yeast) / Strain: ATCC 204508 / S288c |
Molecular weight | Theoretical: 4.145884 KDa |
Sequence | String: MLKRFPTPIL KVYWPFFVAG AAVYYGMSKA ADLSSNT |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 1.5 mg/mL |
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Buffer | pH: 8 / Details: 20 mM Tris-HCl, 150 mM NaCl, pH 8.0 |
Grid | Model: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 400 / Support film - Material: CARBON |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 91 % |
-Electron microscopy
Microscope | FEI TALOS ARCTICA |
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Temperature | Min: 80.0 K / Max: 105.0 K |
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number real images: 9258 / Average electron dose: 8.0 e/Å2 |
Electron beam | Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Calibrated defocus max: 2.8 µm / Calibrated defocus min: 0.8 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.0 mm / Nominal magnification: 36000 |
Sample stage | Specimen holder model: GATAN LIQUID NITROGEN / Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Talos Arctica / Image courtesy: FEI Company |