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

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Basic information

Entry
Database: PDB / ID: 9pfz
TitleArchitecture of human Voltage Dependent Anion Channel 1 in nanodiscs
ComponentsNon-selective voltage-gated ion channel VDAC1
KeywordsMEMBRANE PROTEIN / Beta-barrel / mitochondrial outer membrane protein / lipid bilayer nanodisc
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 / calcium import into the mitochondrion / regulation of autophagy of 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 / calcium import into the mitochondrion / regulation of autophagy of mitochondrion / ceramide binding / mitochondrial permeability transition pore complex / positive regulation of mitophagy / voltage-gated monoatomic ion channel activity / positive regulation of type 2 mitophagy / oxysterol binding / phosphatidylcholine 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 / PINK1-PRKN Mediated Mitophagy / learning / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5.4 Å
AuthorsModaresi, S.M. / Degen, M. / Hiller, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Mol Cells / Year: 2026
Title: Small Molecule Inhibition of VDAC1 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. NADH closes VDAC by ...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. 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 ATP 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 ATP production after impaired mitochondrial function induced by SC18 blockage of VDAC1. Our work set 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, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 27, 2026Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Non-selective voltage-gated ion channel VDAC1


Theoretical massNumber of molelcules
Total (without water)30,8081
Polymers30,8081
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Non-selective voltage-gated ion channel VDAC1 / Outer mitochondrial membrane protein porin 1 / Plasmalemmal porin / Porin 31HL / Porin 31HM / ...Outer mitochondrial membrane protein porin 1 / Plasmalemmal porin / Porin 31HL / Porin 31HM / Voltage-dependent anion-selective channel protein 1 / VDAC-1 / hVDAC1


Mass: 30807.521 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VDAC1, VDAC / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P21796
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: VDAC1 / Type: COMPLEX
Details: Recombinant human VDAC1 reconstituted in lipid bilayer nanodiscs
Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7 / Details: 25 mM NaPi, 100 mM NaCl, pH 7.0
SpecimenConc.: 2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: MSP1D1 nanodiscs with DMPC 14:0 lipids
Specimen supportGrid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil Active R2/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 289 K
Details: 3.0 uL sample, blot time 3sec, Blotforce 1, Blot total 1,

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 45000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 600 nm / Calibrated defocus max: 2500 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 54 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 10 eV
Image scansWidth: 4096 / Height: 4096

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
4cryoSPARCCTF correction
7UCSF ChimeraXmodel fitting
9cryoSPARCinitial Euler assignment
10cryoSPARCfinal Euler assignment
11cryoSPARCclassification
12cryoSPARC3D reconstruction
13UCSF ChimeraXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 5.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 202865 / Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL

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