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- EMDB-71616: Architecture of human Voltage Dependent Anion Channel 1 in nanodiscs -

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Basic information

Entry
Database: EMDB / ID: EMD-71616
TitleArchitecture of human Voltage Dependent Anion Channel 1 in nanodiscs
Map dataCoulomb potential map generated from cryo electron microscopy data of human Voltage Dependent Anion Channel 1
Sample
  • Complex: VDAC1
    • Protein or peptide: Non-selective voltage-gated ion channel VDAC1
KeywordsBeta-barrel / mitochondrial outer membrane protein / lipid bilayer nanodisc / MEMBRANE PROTEIN
Function / homology
Function and homology information


negative regulation of calcium import into the mitochondrion / voltage-gated monoatomic anion channel activity / mitochondrial transmembrane transport / neuron-neuron synaptic transmission / Mitochondrial calcium ion transport / pyruvate biosynthetic process / regulation of autophagy of mitochondrion / calcium import into the mitochondrion / ceramide binding / mitochondrial permeability transition pore complex ...negative regulation of calcium import into the mitochondrion / voltage-gated monoatomic anion channel activity / mitochondrial transmembrane transport / neuron-neuron synaptic transmission / Mitochondrial calcium ion transport / pyruvate biosynthetic process / regulation of autophagy of mitochondrion / calcium import into the mitochondrion / ceramide binding / mitochondrial permeability transition pore complex / positive regulation of mitophagy / voltage-gated monoatomic ion channel activity / positive regulation of type 2 mitophagy / phosphatidylcholine binding / oxysterol binding / Pyruvate metabolism / Mitochondrial protein import / monoatomic anion transport / cholesterol binding / lipid transport / porin activity / pore complex / negative regulation of reactive oxygen species metabolic process / mitochondrial nucleoid / behavioral fear response / epithelial cell differentiation / learning / PINK1-PRKN Mediated Mitophagy / mitochondrial membrane / transmembrane transporter binding / mitochondrial outer membrane / Ub-specific processing proteases / positive regulation of apoptotic process / membrane raft / apoptotic process / synapse / protein kinase binding / negative regulation of apoptotic process / mitochondrion / extracellular exosome / ATP binding / membrane / identical protein binding / nucleus / plasma membrane
Similarity search - Function
Eukaryotic mitochondrial porin signature. / Porin, eukaryotic type / Eukaryotic porin/Tom40 / Eukaryotic porin / Porin domain superfamily
Similarity search - Domain/homology
Non-selective voltage-gated ion channel VDAC1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.4 Å
AuthorsModaresi SM / Degen M / Hiller S
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Mol Cells / Year: 2026
Title: Small molecule inhibition of voltage dependent anion channel 1 reroutes mitochondrial metabolite flux.
Authors: Seyed Majed Modaresi / Leilei Zhang / Amir Ata Saei / Morris Degen / Mohammad Khavani / Hassan Gharibi / Ákos Végvári / Zhiwei Ye / Jie Zhang / Evgeny Pavlov / Elizabeth A Jonas / Kenneth ...Authors: Seyed Majed Modaresi / Leilei Zhang / Amir Ata Saei / Morris Degen / Mohammad Khavani / Hassan Gharibi / Ákos Végvári / Zhiwei Ye / Jie Zhang / Evgeny Pavlov / Elizabeth A Jonas / Kenneth D Tew / Sebastian Hiller / Danyelle M Townsend / Eduardo N Maldonado /
Abstract: Voltage dependent anion channels (VDACs 1, 2 and 3) in the outer mitochondrial membrane control the flux of anions and oxidizable substrates that sustain mitochondrial metabolism. Nicotinamide ...Voltage dependent anion channels (VDACs 1, 2 and 3) in the outer mitochondrial membrane control the flux of anions and oxidizable substrates that sustain mitochondrial metabolism. Nicotinamide adenine dinucleotide (NADH) closes VDAC by binding to a pocket, conserved in all isoforms, located in the inner wall of the channel. Previously, we identified the small molecule SC18 that targets the NADH-binding pocket of VDAC1 employing computational analysis. Here, we explored the interaction between SC18 and VDAC1 using high-resolution nuclear magnetic resonance spectroscopy and molecular dynamics simulations. Atomically resolved data precisely confirmed the computational results, showing that SC18 binds to a site on VDAC1 that partially overlaps with the NADH binding pocket. SC18, in the presence of NADH blocked the conductance of VDAC1 reconstituted in lipid bilayers. To determine the metabolic effect of SC18, we combined readouts of mitochondrial metabolism and glycolysis with functional metabolomics and proteomics. Short-term treatment with SC18 inhibited mitochondrial metabolism and adenosine triphosphate production. Treatment over 24 h and 48 h further reduced mitochondrial uptake of pyruvate and glutamine, utilization of tricarboxylic acid cycle intermediates, as well as lipid, DNA and amino acid synthesis. Concomitant with the inhibition of mitochondrial metabolism, cellular uptake of glucose and glutamine increased in parallel with augmented lactate release. These results indicate that compensatory enhanced glycolysis sustains adenosine triphosphate production after impaired mitochondrial function induced by SC18 blockage of VDAC1. Our work sets a mechanistic foundation for VDAC1 inhibition as a novel strategy to target and reprogram cancer metabolism through modulation of the biosynthetic ability of mitochondria.
History
DepositionJul 7, 2025-
Header (metadata) releaseMay 27, 2026-
Map releaseMay 27, 2026-
UpdateJun 17, 2026-
Current statusJun 17, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_71616.png

Downloads & links

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Map

FileDownload / File: emd_71616.map.gz / Format: CCP4 / Size: 8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCoulomb potential map generated from cryo electron microscopy data of human Voltage Dependent Anion Channel 1
Voxel sizeX=Y=Z: 1.756 Å
Density
Contour LevelBy AUTHOR: 0.124
Minimum - Maximum-0.92233986 - 1.6610198
Average (Standard dev.)-0.00015681413 (±0.04146358)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions128128128
Spacing128128128
CellA=B=C: 224.768 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map A

Fileemd_71616_half_map_1.map
AnnotationHalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_71616_half_map_2.map
AnnotationHalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : VDAC1

EntireName: VDAC1
Components
  • Complex: VDAC1
    • Protein or peptide: Non-selective voltage-gated ion channel VDAC1

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Supramolecule #1: VDAC1

SupramoleculeName: VDAC1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Details: Recombinant human VDAC1 reconstituted in lipid bilayer nanodiscs
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Non-selective voltage-gated ion channel VDAC1

MacromoleculeName: Non-selective voltage-gated ion channel VDAC1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 30.807521 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MAVPPTYADL GKSARDVFTK GYGFGLIKLD LKTKSENGLE FTSSGSANTE TTKVTGSLET KYRWTEYGLT FTEKWNTDNT LGTEITVED QLARGLKLTF DSSFSPNTGK KNAKIKTGYK REHINLGCDM DFDIAGPSIR GALVLGYEGW LAGYQMNFET A KSRVTQSN ...String:
MAVPPTYADL GKSARDVFTK GYGFGLIKLD LKTKSENGLE FTSSGSANTE TTKVTGSLET KYRWTEYGLT FTEKWNTDNT LGTEITVED QLARGLKLTF DSSFSPNTGK KNAKIKTGYK REHINLGCDM DFDIAGPSIR GALVLGYEGW LAGYQMNFET A KSRVTQSN FAVGYKTDEF QLHTNVNDGT EFGGSIYQKV NKKLETAVNL AWTAGNSNTR FGIAAKYQID PDACFSAKVN NS SLIGLGY TQTLKPGIKL TLSALLDGKN VNAGGHKLGL GLEFQA

UniProtKB: Non-selective voltage-gated ion channel VDAC1

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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

Concentration2.0 mg/mL
BufferpH: 7 / Details: 25 mM NaPi, 100 mM NaCl, pH 7.0
GridModel: Quantifoil Active R2/1 / Material: COPPER / Mesh: 200
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 289 K / Instrument: FEI VITROBOT MARK IV
Details: 3.0 uL sample, blot time 3sec, Blotforce 1, Blot total 1,.
DetailsMSP1D1 nanodiscs with DMPC 14:0 lipids

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Electron microscopy

MicroscopeTFS GLACIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Average electron dose: 54.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsCalibrated defocus max: 2.5 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.6 µm / Nominal magnification: 45000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN

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Image processing

CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6tir

Final reconstructionResolution.type: BY AUTHOR / Resolution: 5.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 202865
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationSoftware - Name: cryoSPARC

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

PDB-9pfz:
Architecture of human Voltage Dependent Anion Channel 1 in nanodiscs

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