9FYQ | pdb_00009fyq

Cryo-EM structure of native SV2A in complex with TeNT-Hc, gangliosides and Pro-Macrobody 5

PDB DOI: https://doi.org/10.2210/pdb9FYQ/pdb
EM Map EMD-50889: EMDB EMDataResource

Classification: MEMBRANE PROTEIN
Organism(s): Ovis aries, Clostridium tetani E88, Lama glama, Escherichia coli K-12
Expression System: Escherichia coli K-12
Mutation(s): No

Deposited: 2024-07-03 Released: 2025-05-21
Deposition Author(s): Schenck, S., Brunner, J.D.
Funding Organization(s): Vrije Universiteit Brussel

Experimental Data Snapshot

Method: ELECTRON MICROSCOPY
Resolution: 3.25 Å
Aggregation State: PARTICLE
Reconstruction Method: SINGLE PARTICLE

wwPDB Validation 3D Report Full Report

This is version 1.0 of the entry. See complete history.

Literature

Structures of native SV2A reveal the binding mode for tetanus neurotoxin and anti-epileptic racetams.

Schenck, S., Laeremans, T., Steyaert, J., Brunner, J.D.

(2025) Nat Commun 16: 4172-4172

PubMed: 40325068 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1038/s41467-025-59545-0
Primary Citation of Related Structures:
9FYQ, 9FYR

PubMed 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 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.

Organizational Affiliation

VIB-VUB Center for Structural Biology, VIB, Brussels, Belgium.

Macromolecule Content

Total Structure Weight: 195.38 kDa
Atom Count: 9,181
Modeled Residue Count: 1,121
Deposited Residue Count: 1,701
Unique protein chains: 3

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Synaptic vesicle glycoprotein 2A	A	742	Ovis aries	Mutation(s): 0
UniProt
Find proteins for A0A836APF1 (Ovis aries) Explore A0A836APF1 Go to UniProtKB: A0A836APF1
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	A0A836APF1
Glycosylation
Glycosylation Sites: 3	Glycosylation Focus chain A
Sequence Annotations Expand
Reference Sequence

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(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
Tetanus toxin heavy chain	B [auth C]	469	Clostridium tetani E88	Mutation(s): 0 Gene Names: tetX, CTC_p60 EC: 3.4.24.68
UniProt
Find proteins for P04958 (Clostridium tetani (strain Massachusetts / E88)) Explore P04958 Go to UniProtKB: P04958
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P04958
Sequence Annotations Expand
Reference Sequence

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(by identity cutoff) | 3D Structure

Entity ID: 3
Molecule	Chains	Sequence Length	Organism	Details	Image
Pro-Macrobody 5,Maltose/maltodextrin-binding periplasmic protein	C [auth D]	490	Lama glama, Escherichia coli K-12 This entity is chimeric	Mutation(s): 0
UniProt
Find proteins for P0AEX9 (Escherichia coli (strain K12)) Explore P0AEX9 Go to UniProtKB: P0AEX9
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P0AEX9
Sequence Annotations Expand
Reference Sequence

Oligosaccharides

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Entity ID: 4
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose	D [auth F], E [auth I]	3		N-Glycosylation	Interactions Focus chain D [auth F] Focus chain E [auth I] Interactions & Density Focus chain D [auth F] Focus chain E [auth I]

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
A1IHN (Subject of Investigation/LOI) Query on A1IHN Download Ideal Coordinates CCD File SDF format, chain I [auth C] MOL2 format, chain I [auth C] mmCIF format, chain I [auth C]	I [auth C]	(2~{S},4~{S},5~{R},6~{S})-5-acetamido-2-[(2~{R},3~{R},4~{R},5~{S},6~{R})-2-[(2~{R},3~{R},4~{S},5~{R},6~{S})-2-[(2~{R},3~{S},4~{R},5~{R},6~{R})-4-[(2~{S},4~{S},5~{S},6~{S})-5-acetamido-2-carboxy-4-oxidanyl-6-[(1~{S},2~{R})-1,2,3-tris(oxidanyl)propyl]oxan-2-yl]oxy-6-[(2~{R},3~{S},4~{R},5~{R},6~{R})-6-[2-(docosanoylamino)-3-oxidanyl-octadec-4-enoxy]-2-(hydroxymethyl)-4,5-bis(oxidanyl)oxan-3-yl]oxy-2-(hydroxymethyl)-5-oxidanyl-oxan-3-yl]oxy-6-(hydroxymethyl)-5-oxidanyl-3-(2-oxidanylidenepropyl)oxan-4-yl]oxy-6-(hydroxymethyl)-3,5-bis(oxidanyl)oxan-4-yl]oxy-4-oxidanyl-6-[(1~{R},2~{R})-1,2,3-tris(oxidanyl)propyl]oxane-2-carboxylic acid C₈₉ H₁₅₇ N₃ O₃₉ DSVZLIFOYQBUPU-ZAMVCBRTSA-N		Interactions Focus chain I [auth C] Interactions & Density Focus chain I [auth C]
A1IHM (Subject of Investigation/LOI) Query on A1IHM Download Ideal Coordinates CCD File SDF format, chain H [auth C] MOL2 format, chain H [auth C] mmCIF format, chain H [auth C]	H [auth C]	(2~{R},4~{R},5~{S},6~{S})-2-[(2~{R},3~{R})-3-[(2~{R},3~{S},4~{S},6~{S})-6-[(2~{S},3~{S},4~{R},5~{S},6~{S})-3-[(2~{R},3~{R},4~{R},5~{S},6~{R})-3-acetamido-6-(hydroxymethyl)-4,5-bis(oxidanyl)oxan-2-yl]oxy-2-(hydroxymethyl)-6-[(2~{R},3~{R},4~{R},5~{R},6~{S})-2-(hydroxymethyl)-6-[2-(octadecanoylamino)-3-oxidanyl-octadec-4-enoxy]-4,5-bis(oxidanyl)oxan-3-yl]oxy-5-oxidanyl-oxan-4-yl]oxy-3-azanyl-6-carboxy-4-oxidanyl-oxan-2-yl]-2,3-bis(oxidanyl)propoxy]-5-azanyl-4-oxidanyl-6-[(1~{R},2~{S})-1,2,3-tris(oxidanyl)propyl]oxane-2-carboxylic acid C₇₄ H₁₃₄ N₄ O₃₂ FFILOTSTFMXQJC-UFEOOZISSA-N		Interactions Focus chain H [auth C] Interactions & Density Focus chain H [auth C]
6UZ Query on 6UZ Download Ideal Coordinates CCD File SDF format, chain G [auth A] MOL2 format, chain G [auth A] mmCIF format, chain G [auth A]	G [auth A]	omega-undecylenyl-beta-D-maltopyranoside C₂₃ H₄₂ O₁₁ LFZORGOUSJSBOB-ZNGNCRBCSA-N		Interactions Focus chain G [auth A] Interactions & Density Focus chain G [auth A]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain F [auth A] MOL2 format, chain F [auth A] mmCIF format, chain F [auth A]	F [auth A]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain F [auth A] Interactions & Density Focus chain F [auth A]