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- EMDB-50890: Cryo-EM structure of native SV2A in complex with TeNT-Hc, ganglio... -

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Entry
Database: EMDB / ID: EMD-50890
TitleCryo-EM structure of native SV2A in complex with TeNT-Hc, gangliosides and Pro-Macrobody 5, focused refinement on TeNT-Hc and gangliosides
Map dataLocal refinement on TeNT-Hc and gangliosides
Sample
  • Complex: SV2A bound to TeNT-Hc, gangliosides and Pro-Macrobody 5
    • Complex: Synaptic vesicle glycoprotein 2A
    • Complex: TeNT-Hc
    • Complex: Pro-Macrobody 5
Keywordssynaptic vesicles / MFS transporter / neurotransmission / clostridial neurotoxins / MEMBRANE PROTEIN
Biological speciesOvis aries (sheep) / Clostridium tetani E88 (bacteria) / Lama glama (llama)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.12 Å
AuthorsSchenck S / Brunner JD
Funding support Belgium, 1 items
OrganizationGrant numberCountry
Vrije Universiteit Brussel Belgium
CitationJournal: Nat Commun / Year: 2025
Title: Structures of native SV2A reveal the binding mode for tetanus neurotoxin and anti-epileptic racetams.
Authors: Stephan Schenck / Toon Laeremans / Jan Steyaert / Janine D Brunner /
Abstract: The synaptic vesicle glycoprotein 2A (SV2A) is a synaptic vesicle (SV) resident with homology to the major facilitator superfamily (MFS) and essential in vertebrate neurotransmission. Despite its ...The synaptic vesicle glycoprotein 2A (SV2A) is a synaptic vesicle (SV) resident with homology to the major facilitator superfamily (MFS) and essential in vertebrate neurotransmission. Despite its unclear physiological role, SV2A is of high medical relevance as it is the target of the anti-epileptic drug Levetiracetam (LEV) and a receptor for clostridial neurotoxins (CNTs), among them presumably tetanus neurotoxin (TeNT). To obtain detailed insights about these molecular interactions we subjected native SV2A, purified from brain tissue, to cryo-EM. We discover that TeNT binds SV2A strikingly different from botulinum neurotoxin A and unveil the precise geometry of TeNT binding to dipartite SV2-ganglioside receptors. The structures deliver compelling support for SV2A as the protein receptor for TeNT in central neurons and reinforce the concepts of the dual receptor hypothesis for CNT entry into neurons. Further, our LEV-bound structure of SV2A reveals the drug-interacting residues, delineates a putative substrate pocket in SV2A and provides insights into the SV2-isoform-specificity of LEV. Our work has implications for CNT engineering from a hitherto unrecognized SV2 binding interface and for improved designs of anti-convulsant drugs in epilepsy treatment.
History
DepositionJul 3, 2024-
Header (metadata) releaseMay 21, 2025-
Map releaseMay 21, 2025-
UpdateMay 21, 2025-
Current statusMay 21, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_50890.png

Downloads & links

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Map

FileDownload / File: emd_50890.map.gz / Format: CCP4 / Size: 343 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationLocal refinement on TeNT-Hc and gangliosides
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.71 Å/pix.
x 448 pix.
= 318.08 Å		0.71 Å/pix.
x 448 pix.
= 318.08 Å		0.71 Å/pix.
x 448 pix.
= 318.08 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.71 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0567
Minimum - Maximum-0.18295024 - 0.3608618
Average (Standard dev.)0.000310542 (±0.0077392044)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions448448448
Spacing448448448
CellA=B=C: 318.08 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_50890_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Phenix-density modified map used for model building of...

Fileemd_50890_additional_1.map
AnnotationPhenix-density modified map used for model building of TeNT-Hc and gangliosides
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map A

Fileemd_50890_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_50890_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 : SV2A bound to TeNT-Hc, gangliosides and Pro-Macrobody 5

EntireName: SV2A bound to TeNT-Hc, gangliosides and Pro-Macrobody 5
Components
  • Complex: SV2A bound to TeNT-Hc, gangliosides and Pro-Macrobody 5
    • Complex: Synaptic vesicle glycoprotein 2A
    • Complex: TeNT-Hc
    • Complex: Pro-Macrobody 5

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Supramolecule #1: SV2A bound to TeNT-Hc, gangliosides and Pro-Macrobody 5

SupramoleculeName: SV2A bound to TeNT-Hc, gangliosides and Pro-Macrobody 5
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 / Details: Focused refinement on TeNT-Hc and gangliosides
Source (natural)Organism: Ovis aries (sheep)
Molecular weightTheoretical: 53.6 KDa

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Supramolecule #2: Synaptic vesicle glycoprotein 2A

SupramoleculeName: Synaptic vesicle glycoprotein 2A / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Ovis aries (sheep)

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Supramolecule #3: TeNT-Hc

SupramoleculeName: TeNT-Hc / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Clostridium tetani E88 (bacteria)

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Supramolecule #4: Pro-Macrobody 5

SupramoleculeName: Pro-Macrobody 5 / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: Lama glama (llama)

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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

Concentration7 mg/mL
BufferpH: 7.5
Details: 10 mM Hepes-NaOH 7.5, 150 mM NaCl, 3 mM maltose, 0.03 % n-dodecyl-beta-D-maltopyranoside, 0.006% cholesterol hemisuccinate
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 293 K / Instrument: GATAN CRYOPLUNGE 3

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Electron microscopy

MicroscopeJEOL CRYO ARM 300
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number real images: 22295 / Average exposure time: 2.796 sec. / Average electron dose: 60.0 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: 0.8 µm / Nominal magnification: 60000
Sample stageSpecimen holder model: JEOL CRYOSPECPORTER / Cooling holder cryogen: NITROGEN

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Image processing

CTF correctionSoftware - Name: cryoSPARC (ver. cryoSPARC-v.4) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.12 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. cryoSPARC-v.4) / Number images used: 162694
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL

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