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- EMDB-36631: Cryo-EM structure of Mycobacterium tuberculosis ATP synthase F1 i... -

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Basic information

Entry
Database: EMDB / ID: EMD-36631
TitleCryo-EM structure of Mycobacterium tuberculosis ATP synthase F1 in complex with TBAJ-587
Map data
Sample
  • Complex: Mycobacterium tuberculosis ATP synthase
KeywordsATP synthase / Mycobacterium tuberculosis / cryo-EM / MEMBRANE PROTEIN
Biological speciesMycobacterium tuberculosis (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.8 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
DepositionJun 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_36631.png

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Map

FileDownload / File: emd_36631.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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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

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.73 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.47074658 - 0.8535786
Average (Standard dev.)-0.000009167563 (±0.025935477)
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: #1

Fileemd_36631_half_map_1.map
Projections & Slices
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Half map: #2

Fileemd_36631_half_map_2.map
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Sample components

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Entire : Mycobacterium tuberculosis ATP synthase

EntireName: Mycobacterium tuberculosis ATP synthase
Components
  • Complex: Mycobacterium tuberculosis ATP synthase

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Supramolecule #1: Mycobacterium tuberculosis ATP synthase

SupramoleculeName: Mycobacterium tuberculosis ATP synthase / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Mycobacterium tuberculosis (bacteria)

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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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
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: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 81528
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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