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- EMDB-37440: Cryo-EM structure of the inhibitor-bound Vo complex from Enteroco... -

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Basic information

Entry
Database: EMDB / ID: EMD-37440
TitleCryo-EM structure of the inhibitor-bound Vo complex from Enterococcus hirae
Map data
Sample
  • Complex: V-ATPase
    • Protein or peptide: V-type sodium ATPase subunit K
    • Protein or peptide: V-type sodium ATPase subunit I
  • Ligand: CARDIOLIPIN
  • Ligand: SODIUM ION
  • Ligand: N,N-dimethyl-4-(5-methyl-1H-benzimidazol-2-yl)aniline
  • Ligand: water
KeywordsV-ATPase / Na+-transporting / membrane protein / ATP hydrolyses / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


proton-transporting V-type ATPase, V0 domain / vacuolar proton-transporting V-type ATPase complex / vacuolar acidification / sodium ion transport / proton-transporting ATPase activity, rotational mechanism / ATPase binding / identical protein binding / plasma membrane
Similarity search - Function
V-ATPase proteolipid subunit / V-type ATPase, V0 complex, 116kDa subunit family / V-type ATPase 116kDa subunit family / V-ATPase proteolipid subunit C-like domain / F/V-ATP synthase subunit C superfamily / ATP synthase subunit C
Similarity search - Domain/homology
V-type sodium ATPase subunit I / V-type sodium ATPase subunit K
Similarity search - Component
Biological speciesEnterococcus hirae ATCC 9790 (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.2 Å
AuthorsSuzuki K / Mikuriya S / Adachi N / Kawasaki M / Senda T / Moriya T / Murata T
Funding support Japan, 2 items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS) Japan
Japan Agency for Medical Research and Development (AMED) Japan
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: Na-V-ATPase inhibitor curbs VRE growth and unveils Na pathway structure.
Authors: Kano Suzuki / Yoshiyuki Goto / Akihiro Otomo / Kouki Shimizu / Shohei Abe / Katsuhiko Moriyama / Satoshi Yasuda / Yusuke Hashimoto / Jun Kurushima / Sho Mikuriya / Fabiana L Imai / Naruhiko ...Authors: Kano Suzuki / Yoshiyuki Goto / Akihiro Otomo / Kouki Shimizu / Shohei Abe / Katsuhiko Moriyama / Satoshi Yasuda / Yusuke Hashimoto / Jun Kurushima / Sho Mikuriya / Fabiana L Imai / Naruhiko Adachi / Masato Kawasaki / Yumi Sato / Satoshi Ogasawara / So Iwata / Toshiya Senda / Mitsunori Ikeguchi / Haruyoshi Tomita / Ryota Iino / Toshio Moriya / Takeshi Murata /
Abstract: Vancomycin-resistant Enterococcus faecium (VRE) is a major cause of nosocomial infections, particularly endocarditis and sepsis. With the diminishing effectiveness of antibiotics against VRE, new ...Vancomycin-resistant Enterococcus faecium (VRE) is a major cause of nosocomial infections, particularly endocarditis and sepsis. With the diminishing effectiveness of antibiotics against VRE, new antimicrobial agents are urgently needed. Our previous research demonstrated the crucial role of Na-transporting V-ATPase in Enterococcus hirae for growth under alkaline conditions. In this study, we identified a compound, V-161, from 70,600 compounds, which markedly inhibits E. hirae V-ATPase activity. V-161 not only inhibits VRE growth in alkaline conditions but also significantly suppresses VRE colonization in the mouse small intestine. Furthermore, we unveiled the high-resolution structure of the membrane V part due to V-161 binding. V-161 binds to the interface of the c-ring and a-subunit, constituting the Na transport pathway in the membrane, thereby halting its rotation. This structural insight presents potential avenues for developing therapeutic agents for VRE treatment and elucidates the Na transport pathway and mechanism.
History
DepositionSep 12, 2023-
Header (metadata) releaseOct 9, 2024-
Map releaseOct 9, 2024-
UpdateApr 23, 2025-
Current statusApr 23, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_37440.png

Downloads & links

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Map

FileDownload / File: emd_37440.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.)
0.83 Å/pix.
x 512 pix.
= 424.96 Å		0.83 Å/pix.
x 512 pix.
= 424.96 Å		0.83 Å/pix.
x 512 pix.
= 424.96 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.034
Minimum - Maximum-0.07593882 - 0.14145127
Average (Standard dev.)0.0000109935645 (±0.0042770994)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 424.96 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_37440_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_37440_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_37440_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : V-ATPase

EntireName: V-ATPase
Components
  • Complex: V-ATPase
    • Protein or peptide: V-type sodium ATPase subunit K
    • Protein or peptide: V-type sodium ATPase subunit I
  • Ligand: CARDIOLIPIN
  • Ligand: SODIUM ION
  • Ligand: N,N-dimethyl-4-(5-methyl-1H-benzimidazol-2-yl)aniline
  • Ligand: water

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Supramolecule #1: V-ATPase

SupramoleculeName: V-ATPase / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Enterococcus hirae ATCC 9790 (bacteria)
Molecular weightTheoretical: 735 KDa

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Macromolecule #1: V-type sodium ATPase subunit K

MacromoleculeName: V-type sodium ATPase subunit K / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO
Source (natural)Organism: Enterococcus hirae ATCC 9790 (bacteria)
Molecular weightTheoretical: 16.043918 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MMDYLITQNG GMVFAVLAMA TATIFSGIGS AKGVGMTGEA AAALTTSQPE KFGQALILQL LPGTQGLYGF VIAFLIFINL GSDMSVVQG LNFLGASLPI AFTGLFSGIA QGKVAAAGIQ ILAKKPEHAT KGIIFAAMVE TYAILGFVIS FLLVLNA

UniProtKB: V-type sodium ATPase subunit K

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Macromolecule #2: V-type sodium ATPase subunit I

MacromoleculeName: V-type sodium ATPase subunit I / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Enterococcus hirae ATCC 9790 (bacteria)
Molecular weightTheoretical: 76.5155 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MAVTKMEKVT LISDKKNREI LLQAVQGLHA VEIRDLFQES ENNQWVETFF PEPEMIDKDK ELAKLSYKLT DIRTAIQFIE HHGEKSQKK QHLKRRELSL DTLEKNYSEE AFSKKLEEVL LLKEQWEQLV DERQQLEDQE NWLLNWQNLD LAPKAFDSQM T KLVIGTVN ...String:
MAVTKMEKVT LISDKKNREI LLQAVQGLHA VEIRDLFQES ENNQWVETFF PEPEMIDKDK ELAKLSYKLT DIRTAIQFIE HHGEKSQKK QHLKRRELSL DTLEKNYSEE AFSKKLEEVL LLKEQWEQLV DERQQLEDQE NWLLNWQNLD LAPKAFDSQM T KLVIGTVN AKNAESFKAE VAEINEAYLE EINSSPTTTY FAYIVLRADE SRMEEIASRY GFVKEDYLYE GTPQQQLVAA KQ SLQEIKD QQKKLSSAIG ACSGYIKDFE WTEEIFLARS EREAIKDRII HTPYLILIQG WVDHEEKQEL IHMLQNILAS EEV YLTFDE PTDNEIAEEV PTKLKNHPIV APFEMLTEMY SLPKYEEVDP TPWMMPFYLV FFGMMVADIG YGLLMFLGAF LLQK LVVLP RGMQRFAKFF EILAIPSIIW GFIYSSFFGA ALPKEIFGIH LPFPILSTTD DVNTILILSV IFGLIQILVG LFIAA KEHI KRKAYVDAVN DGFAWQGILL GIILILLGTM ILKNNAFVYL GGALAVLSAV CILIIPVFQS SSKAKGIAKG AYNLYG LTG YIGDLVSYTR LMALGISGGS IAAAFNMLVA FMPPAARFSV GILLIIVLQA LNMFLTLLSA YVHGARLQYV EFFGKFY TG GGRSFKPLKT VEKYVNINHK KKEHLYFQGG

UniProtKB: V-type sodium ATPase subunit I

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Macromolecule #3: CARDIOLIPIN

MacromoleculeName: CARDIOLIPIN / type: ligand / ID: 3 / Number of copies: 5 / Formula: CDL
Molecular weightTheoretical: 1.464043 KDa
Chemical component information

ChemComp-CDL:
CARDIOLIPIN / phospholipid*YM

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Macromolecule #4: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 4 / Number of copies: 9
Molecular weightTheoretical: 22.99 Da

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Macromolecule #5: N,N-dimethyl-4-(5-methyl-1H-benzimidazol-2-yl)aniline

MacromoleculeName: N,N-dimethyl-4-(5-methyl-1H-benzimidazol-2-yl)aniline / type: ligand / ID: 5 / Number of copies: 1 / Formula: W3K
Molecular weightTheoretical: 251.326 Da

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Macromolecule #6: water

MacromoleculeName: water / type: ligand / ID: 6 / Number of copies: 224 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

Concentration6 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
100.0 mMNaClsodium chloride
50.0 mMTris-HClTris hydrochloride acid
5.0 mMMgSO4magnesium sulfate
0.005 %LMNGlauryl maltose neopentyl glycol
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 15 eV
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 49.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1008654
Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 2.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1.3) / Number images used: 225359
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1.3)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1.3)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChainDetails

2bl2

source_name: PDB, initial_model_type: experimental model
source_name: SwissModel6LY9
source_name: SwissModel6M0S
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-8wci:
Cryo-EM structure of the inhibitor-bound Vo complex from Enterococcus hirae

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