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- EMDB-35983: Cryo-EM structure of Mycobacterium tuberculosis ATP synthase Fo i... -

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Basic information

Entry
Database: EMDB / ID: EMD-35983
TitleCryo-EM structure of Mycobacterium tuberculosis ATP synthase Fo in the apo-form
Map data
Sample
  • Complex: Mycobacterium tuberculosis ATP synthase Fo in the apo-form
    • Protein or peptide: ATP synthase subunit c
    • Protein or peptide: ATP synthase subunit a
KeywordsATP synthase / Mycobacterium tuberculosis / cryo-EM / MEMBRANE PROTEIN
Function / homology
Function and homology information


proton-transporting ATP synthase complex, coupling factor F(o) / proton-transporting ATP synthase activity, rotational mechanism / hydrolase activity / lipid binding / plasma membrane
Similarity search - Function
ATP synthase, F0 complex, subunit A, bacterial/chloroplast / 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. / ATP synthase, F0 complex, subunit C / F1F0 ATP synthase subunit C superfamily / ATP synthase, F0 complex, subunit C, DCCD-binding site ...ATP synthase, F0 complex, subunit A, bacterial/chloroplast / 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. / 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 c / ATP synthase subunit a
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.15 Å
AuthorsZhang Y / Lai Y / Liu F / Rao Z / Gong H
Funding support China, 3 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81520108019 China
National Natural Science Foundation of China (NSFC)32100976 China
National Natural Science Foundation of China (NSFC)82222042 China
CitationJournal: Nature / Year: 2024
Title: Inhibition of M. tuberculosis and human ATP synthase by BDQ and TBAJ-587.
Authors: Yuying Zhang / Yuezheng Lai / Shan Zhou / Ting Ran / Yue Zhang / Ziqing Zhao / Ziyan Feng / Long Yu / Jinxu Xu / Kun Shi / Jianyun Wang / Yu Pang / Liang Li / Hongming Chen / Luke W Guddat / ...Authors: Yuying Zhang / Yuezheng Lai / Shan Zhou / Ting Ran / Yue Zhang / Ziqing Zhao / Ziyan Feng / Long Yu / Jinxu Xu / Kun Shi / Jianyun Wang / Yu Pang / Liang Li / Hongming Chen / Luke W Guddat / Yan Gao / Fengjiang Liu / Zihe Rao / Hongri Gong /
Abstract: Bedaquiline (BDQ), a first-in-class diarylquinoline anti-tuberculosis drug, and its analogue, TBAJ-587, prevent the growth and proliferation of Mycobacterium tuberculosis by inhibiting ATP synthase. ...Bedaquiline (BDQ), a first-in-class diarylquinoline anti-tuberculosis drug, and its analogue, TBAJ-587, prevent the growth and proliferation of Mycobacterium tuberculosis by inhibiting ATP synthase. However, BDQ also inhibits human ATP synthase. At present, how these compounds interact with either M. tuberculosis ATP synthase or human ATP synthase is unclear. Here we present cryogenic electron microscopy structures of M. tuberculosis ATP synthase with and without BDQ and TBAJ-587 bound, and human ATP synthase bound to BDQ. The two inhibitors interact with subunit a and the c-ring at the leading site, c-only sites and lagging site in M. tuberculosis ATP synthase, showing that BDQ and TBAJ-587 have similar modes of action. The quinolinyl and dimethylamino units of the compounds make extensive contacts with the protein. The structure of human ATP synthase in complex with BDQ reveals that the BDQ-binding site is similar to that observed for the leading site in M. tuberculosis ATP synthase, and that the quinolinyl unit also interacts extensively with the human enzyme. This study will improve researchers' understanding of the similarities and differences between human ATP synthase and M. tuberculosis ATP synthase in terms of the mode of BDQ binding, and will allow the rational design of novel diarylquinolines as anti-tuberculosis drugs.
History
DepositionApr 21, 2023-
Header (metadata) releaseMay 1, 2024-
Map releaseMay 1, 2024-
UpdateAug 21, 2024-
Current statusAug 21, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_35983.png

Downloads & links

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Map

FileDownload / File: emd_35983.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 512 pix.
= 373.76 Å		0.73 Å/pix.
x 512 pix.
= 373.76 Å		0.73 Å/pix.
x 512 pix.
= 373.76 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.73 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.4364862 - 0.75922567
Average (Standard dev.)-0.0001108207 (±0.015278869)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 373.76 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_35983_half_map_1.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_35983_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Mycobacterium tuberculosis ATP synthase Fo in the apo-form

EntireName: Mycobacterium tuberculosis ATP synthase Fo in the apo-form
Components
  • Complex: Mycobacterium tuberculosis ATP synthase Fo in the apo-form
    • Protein or peptide: ATP synthase subunit c
    • Protein or peptide: ATP synthase subunit a

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Supramolecule #1: Mycobacterium tuberculosis ATP synthase Fo in the apo-form

SupramoleculeName: Mycobacterium tuberculosis ATP synthase Fo in the apo-form
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mycobacterium tuberculosis (bacteria)

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Macromolecule #1: ATP synthase subunit c

MacromoleculeName: ATP synthase subunit c / type: protein_or_peptide / ID: 1 / Number of copies: 9 / Enantiomer: LEVO
Source (natural)Organism: Mycobacterium tuberculosis (bacteria)
Molecular weightTheoretical: 8.058423 KDa
Recombinant expressionOrganism: Mycolicibacterium smegmatis (bacteria)
SequenceString:
MDPTIAAGAL IGGGLIMAGG AIGAGIGDGV AGNALISGVA RQPEAQGRLF TPFFITVGLV EAAYFINLAF MALFVFATPV K

UniProtKB: ATP synthase subunit c

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Macromolecule #2: ATP synthase subunit a

MacromoleculeName: ATP synthase subunit a / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mycobacterium tuberculosis (bacteria)
Molecular weightTheoretical: 27.488436 KDa
Recombinant expressionOrganism: Mycolicibacterium smegmatis (bacteria)
SequenceString: MTETILAAQI EVGEHHTATW LGMTVNTDTV LSTAIAGLIV IALAFYLRAK VTSTDVPGGV QLFFEAITIQ MRNQVESAIG MRIAPFVLP LAVTIFVFIL ISNWLAVLPV QYTDKHGHTT ELLKSAAADI NYVLALALFV FVCYHTAGIW RRGIVGHPIK L LKGHVTLL ...String:
MTETILAAQI EVGEHHTATW LGMTVNTDTV LSTAIAGLIV IALAFYLRAK VTSTDVPGGV QLFFEAITIQ MRNQVESAIG MRIAPFVLP LAVTIFVFIL ISNWLAVLPV QYTDKHGHTT ELLKSAAADI NYVLALALFV FVCYHTAGIW RRGIVGHPIK L LKGHVTLL APINLVEEVA KPISLSLRLF GNIFAGGILV ALIALFPPYI MWAPNAIWKA FDLFVGAIQA FIFALLTILY FS QAMELEE EHH

UniProtKB: ATP synthase subunit a

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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

BufferpH: 7.4
GridModel: Quantifoil R1.2/1.3 / Material: COPPER
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris X / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: AlphaFold
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.15 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 66593
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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