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- EMDB-29652: Cryo-EM structure of TBAJ-876-bound Mycobacterium smegmatis ATP s... -
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Basic information
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Title | Cryo-EM structure of TBAJ-876-bound Mycobacterium smegmatis ATP synthase FO region | |||||||||
![]() | Cryo-EM structure of TBAJ-876-bound Mycobacterium smegmatis ATP synthase FO region (sharpened) | |||||||||
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![]() | ATP synthase / mycobacterial / inhibitor / tuberculosis / antibiotic / HYDROLASE / TRANSLOCASE-INHIBITOR complex | |||||||||
Function / homology | ![]() proton motive force-driven plasma membrane ATP synthesis / photosynthetic electron transport in photosystem I / proton-transporting ATP synthase complex, coupling factor F(o) / photosynthetic electron transport in photosystem II / proton-transporting ATP synthase complex, catalytic core F(1) / proton-transporting ATPase activity, rotational mechanism / proton-transporting ATP synthase activity, rotational mechanism / hydrolase activity / lipid binding / plasma membrane Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.8 Å | |||||||||
![]() | Courbon GM / Rubinstein JL | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Mechanism of mycobacterial ATP synthase inhibition by squaramides and second generation diarylquinolines. Authors: Gautier M Courbon / Paul R Palme / Lea Mann / Adrian Richter / Peter Imming / John L Rubinstein / ![]() ![]() Abstract: Mycobacteria, such as Mycobacterium tuberculosis, depend on the activity of adenosine triphosphate (ATP) synthase for growth. The diarylquinoline bedaquiline (BDQ), a mycobacterial ATP synthase ...Mycobacteria, such as Mycobacterium tuberculosis, depend on the activity of adenosine triphosphate (ATP) synthase for growth. The diarylquinoline bedaquiline (BDQ), a mycobacterial ATP synthase inhibitor, is an important medication for treatment of drug-resistant tuberculosis but suffers from off-target effects and is susceptible to resistance mutations. Consequently, both new and improved mycobacterial ATP synthase inhibitors are needed. We used electron cryomicroscopy and biochemical assays to study the interaction of Mycobacterium smegmatis ATP synthase with the second generation diarylquinoline TBAJ-876 and the squaramide inhibitor SQ31f. The aryl groups of TBAJ-876 improve binding compared with BDQ, while SQ31f, which blocks ATP synthesis ~10 times more potently than ATP hydrolysis, binds a previously unknown site in the enzyme's proton-conducting channel. Remarkably, BDQ, TBAJ-876, and SQ31f all induce similar conformational changes in ATP synthase, suggesting that the resulting conformation is particularly suited for drug binding. Further, high concentrations of the diarylquinolines uncouple the transmembrane proton motive force while for SQ31f they do not, which may explain why high concentrations of diarylquinolines, but not SQ31f, have been reported to kill mycobacteria. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 117.9 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 18.8 KB 18.8 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 10.5 KB | Display | ![]() |
Images | ![]() | 80.3 KB | ||
Filedesc metadata | ![]() | 5.7 KB | ||
Others | ![]() ![]() | 115.8 MB 115.8 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8g0bMC ![]() 8g07C ![]() 8g08C ![]() 8g09C ![]() 8g0aC ![]() 8g0cC ![]() 8g0dC ![]() 8g0eC C: citing same article ( M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | Cryo-EM structure of TBAJ-876-bound Mycobacterium smegmatis ATP synthase FO region (sharpened) | ||||||||||||||||||||
Voxel size | X=Y=Z: 1.03 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: Cryo-EM structure of TBAJ-876-bound Mycobacterium smegmatis ATP synthase...
File | emd_29652_half_map_1.map | ||||||||||||
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Annotation | Cryo-EM structure of TBAJ-876-bound Mycobacterium smegmatis ATP synthase FO region (Half A) | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Cryo-EM structure of TBAJ-876-bound Mycobacterium smegmatis ATP synthase...
File | emd_29652_half_map_2.map | ||||||||||||
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Annotation | Cryo-EM structure of TBAJ-876-bound Mycobacterium smegmatis ATP synthase FO region (Half B) | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
-Entire : TBAJ-876-bound Mycobacterium smegmatis ATP synthase FO region
Entire | Name: TBAJ-876-bound Mycobacterium smegmatis ATP synthase FO region |
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Components |
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-Supramolecule #1: TBAJ-876-bound Mycobacterium smegmatis ATP synthase FO region
Supramolecule | Name: TBAJ-876-bound Mycobacterium smegmatis ATP synthase FO region type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4 |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: ATP synthase subunit c
Macromolecule | Name: ATP synthase subunit c / type: protein_or_peptide / ID: 1 / Number of copies: 9 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 8.597982 KDa |
Sequence | String: MDLDPNAIIT AGALIGGGLI MGGGAIGAGI GDGIAGNALI SGIARQPEAQ GRLFTPFFIT VGLVEAAYFI NLAFMALFVF ATPGLQ UniProtKB: ATP synthase subunit c |
-Macromolecule #2: ATP synthase subunit a
Macromolecule | Name: ATP synthase subunit a / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 27.568482 KDa |
Sequence | String: 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 |
-Macromolecule #3: ATP synthase subunit b
Macromolecule | Name: ATP synthase subunit b / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 17.636701 KDa |
Sequence | String: MGEFSATILA ASQAAEEGGG GSNFLIPNGT FFAVLIIFLI VLGVISKWVV PPISKVLAER EAMLAKTAAD NRKSAEQVAA AQADYEKEM AEARAQASAL RDEARAAGRS VVDEKRAQAS GEVAQTLTQA DQQLSAQGDQ VRSGLESSVD GLSAKLASRI L GVDVNSGG TQ UniProtKB: ATP synthase subunit b |
-Macromolecule #4: ATP synthase subunit b-delta
Macromolecule | Name: ATP synthase subunit b-delta / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 47.504723 KDa |
Sequence | String: 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 |
-Macromolecule #5: (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridi...
Macromolecule | Name: (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2,3,6-trimethoxypyridin-4-yl)butan-2-ol type: ligand / ID: 5 / Number of copies: 7 / Formula: YGR |
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Molecular weight | Theoretical: 657.552 Da |
Chemical component information | ![]() ChemComp-YGR: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 44.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.1 µm / Nominal defocus min: 0.7000000000000001 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |