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- EMDB-71500: Structure of Synaptic Vesicle Protein 2A Bound to UCB7361 -

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Basic information

Entry
Database: EMDB / ID: EMD-71500
TitleStructure of Synaptic Vesicle Protein 2A Bound to UCB7361
Map dataSharpened map
Sample
  • Complex: SV2A bound to UCB7361
    • Protein or peptide: Synaptic vesicle glycoprotein 2A
  • Ligand: (4S)-1-{[(4S)-2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(3,3,3-trifluoropropyl)pyrrolidin-2-one
KeywordsSynaptic vesicle / SLC22 / Inhibitor / MEMBRANE PROTEIN
Function / homology
Function and homology information


Toxicity of botulinum toxin type F (botF) / Toxicity of botulinum toxin type D (botD) / Toxicity of botulinum toxin type E (botE) / Toxicity of botulinum toxin type A (botA) / presynaptic active zone / synaptic vesicle priming / transmembrane transporter activity / neuromuscular junction / GABA-ergic synapse / intracellular calcium ion homeostasis ...Toxicity of botulinum toxin type F (botF) / Toxicity of botulinum toxin type D (botD) / Toxicity of botulinum toxin type E (botE) / Toxicity of botulinum toxin type A (botA) / presynaptic active zone / synaptic vesicle priming / transmembrane transporter activity / neuromuscular junction / GABA-ergic synapse / intracellular calcium ion homeostasis / synaptic vesicle / cell-cell junction / synaptic vesicle membrane / neuron projection / protein kinase binding / glutamatergic synapse / endoplasmic reticulum / plasma membrane
Similarity search - Function
: / SV2A/B/C luminal domain / Synaptic vesicle protein SV2 / Sugar transporter, conserved site / Major facilitator, sugar transporter-like / Sugar (and other) transporter / Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
Synaptic vesicle glycoprotein 2A
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.91 Å
AuthorsMittal A / Martin MF / Ledecq M / Horanyi PS / Coleman JA
Funding support United States, 1 items
OrganizationGrant numberCountry
Brain & Behavior Research Foundation30153 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Mechanisms underlying allosteric modulation of antiseizure medication binding to synaptic vesicle protein 2A (SV2A).
Authors: Anshumali Mittal / Matthew F Martin / Laurent Provins / Adrian Hall / Marie Ledecq / Christian Wolff / Michel Gillard / Peter S Horanyi / Jonathan A Coleman /
Abstract: Brivaracetam (BRV) and levetiracetam (LEV) are antiseizure medications (ASMs); UCB-J is a PET tracer targeting synaptic vesicle protein 2A (SV2A); UCB7361 is closely related to padsevonil, an ...Brivaracetam (BRV) and levetiracetam (LEV) are antiseizure medications (ASMs); UCB-J is a PET tracer targeting synaptic vesicle protein 2A (SV2A); UCB7361 is closely related to padsevonil, an experimental anticonvulsant; while UCB1244283 acts as an allosteric modulator for BRV and LEV binding but not for these other ligands. The SV2A-BRV-UCB1244283 structure reveals how UCB1244283 allosterically enhances BRV binding by occupying an allosteric site near the primary binding site, preventing BRV dissociation. This allosteric site, formed by hydrophobic and uncharged residues, is an uncharacterized small-molecule binding site in SV2A. Structural analysis and mutagenesis demonstrate that an allosteric network between the primary and allosteric sites governs high-affinity ASM binding. Our studies suggest that UCB1244283 selectively binds SV2A over SV2B and SV2C, with specific mutations disrupting binding. Structures of SV2A-UCB-J and SV2A-UCB7361 show that UCB1244283 binding is only possible when the primary site ligand does not overlap with the allosteric site, and that repositioning of Ser601, Thr605, and Leu655 is critical for allosteric ligand binding. Structural comparison of multiple SV2A complexes reveals that primary site occupancy shapes the conformation of the lumenal half of the transmembrane domain, influencing how UCB1244283 binds via a connected network that differentially stabilizes TM1 in either an open or closed conformation and repositions key allosteric and primary site residues. These insights provide a foundation for developing therapeutics targeting the allosteric site and modulating SV2A function.
History
DepositionJun 27, 2025-
Header (metadata) releaseSep 10, 2025-
Map releaseSep 10, 2025-
UpdateOct 1, 2025-
Current statusOct 1, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_71500.png

Downloads & links

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Map

FileDownload / File: emd_71500.map.gz / Format: CCP4 / Size: 144.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.72 Å/pix.
x 336 pix.
= 241.584 Å		0.72 Å/pix.
x 336 pix.
= 241.584 Å		0.72 Å/pix.
x 336 pix.
= 241.584 Å

Surface

Projections

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Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.719 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.1
Minimum - Maximum-4.613782 - 5.3419724
Average (Standard dev.)-0.0019727089 (±0.15736124)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions336336336
Spacing336336336
CellA=B=C: 241.584 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_71500_msk_1.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Additional map: Unsharpened map

Fileemd_71500_additional_1.map
AnnotationUnsharpened map
Projections & Slices
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Half map: Half map A

Fileemd_71500_half_map_1.map
AnnotationHalf map A
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_71500_half_map_2.map
AnnotationHalf map B
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Sample components

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Entire : SV2A bound to UCB7361

EntireName: SV2A bound to UCB7361
Components
  • Complex: SV2A bound to UCB7361
    • Protein or peptide: Synaptic vesicle glycoprotein 2A
  • Ligand: (4S)-1-{[(4S)-2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(3,3,3-trifluoropropyl)pyrrolidin-2-one

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Supramolecule #1: SV2A bound to UCB7361

SupramoleculeName: SV2A bound to UCB7361 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 75.5 kDa/nm

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Macromolecule #1: Synaptic vesicle glycoprotein 2A

MacromoleculeName: Synaptic vesicle glycoprotein 2A / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 82.777031 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MEEGFRDRAA FIRGAKDIAK EVKKHAAKKV VKGLDRVQDE YSRRSYSRFE EEDDDDDFPA PSDGYYRGEG TQDEEEGGAS SDATEGHDE DDEIYEGEYQ GIPRAESGGK GERMADGAPL AGVRGGLSDG EGPPGGRGEA QRRKEREELA QQYEAILREC G HGRFQWTL ...String:
MEEGFRDRAA FIRGAKDIAK EVKKHAAKKV VKGLDRVQDE YSRRSYSRFE EEDDDDDFPA PSDGYYRGEG TQDEEEGGAS SDATEGHDE DDEIYEGEYQ GIPRAESGGK GERMADGAPL AGVRGGLSDG EGPPGGRGEA QRRKEREELA QQYEAILREC G HGRFQWTL YFVLGLALMA DGVEVFVVGF VLPSAEKDMC LSDSNKGMLG LIVYLGMMVG AFLWGGLADR LGRRQCLLIS LS VNSVFAF FSSFVQGYGT FLFCRLLSGV GIGGSIPIVF SYFSEFLAQE KRGEHLSWLC MFWMIGGVYA AAMAWAIIPH YGW SFQMGS AYQFHSWRVF VLVCAFPSVF AIGALTTQPE SPRFFLENGK HDEAWMVLKQ VHDTNMRAKG HPERVFSVTH IKTI HQEDE LIEIQSDTGT WYQRWGVRAL SLGGQVWGNF LSCFGPEYRR ITLMMMGVWF TMSFSYYGLT VWFPDMIRHL QAVDY ASRT KVFPGERVEH VTFNFTLENQ IHRGGQYFND KFIGLRLKSV SFEDSLFEEC YFEDVTSSNT FFRNCTFINT VFYNTD LFE YKFVNSRLIN STFLHNKEGC PLDVTGTGEG AYMVYFVSFL GTLAVLPGNI VSALLMDKIG RLRMLAGSSV MSCVSCF FL SFGNSESAMI ALLCLFGGVS IASWNALDVL TVELYPSDKR TTAFGFLNAL CKLAAVLGIS IFTSFVGITK AAPILFAS A ALALGSSLAL KLPETRGQVL Q

UniProtKB: Synaptic vesicle glycoprotein 2A

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Macromolecule #2: (4S)-1-{[(4S)-2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b]...

MacromoleculeName: (4S)-1-{[(4S)-2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(3,3,3-trifluoropropyl)pyrrolidin-2-one
type: ligand / ID: 2 / Number of copies: 1 / Formula: A1CHN
Molecular weightTheoretical: 430.369 Da

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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

Concentration7.5 mg/mL
BufferpH: 8
GridModel: Quantifoil R2/1 / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 298 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 194000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

8uo9


Details: Structure of synaptic vesicle protein 2A in complex with a nanobody. PDB DOI: https://doi.org/10.2210/pdb8UO9/pdbEM Map EMD-42431: EMDB EMDataResource Deposited: 2023-10-19 Released: 2024-05- ...Details: Structure of synaptic vesicle protein 2A in complex with a nanobody. PDB DOI: https://doi.org/10.2210/pdb8UO9/pdbEM Map EMD-42431: EMDB EMDataResource Deposited: 2023-10-19 Released: 2024-05-22 Deposition Author(s): Mittal, A., Martin, M.F., Levin, E., Adams, C., Yang, M., Ledecq, M., Horanyi, P.S., Coleman, J.A.
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.91 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 22999
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

8uo9


Chain - Chain ID: A / Chain - Residue range: 144-738 / Chain - Source name: PDB / Chain - Initial model type: experimental model / Details: PDB 8UO9 was used for building initial model.
SoftwareName: Coot (ver. 0.9.8.95 EL) / Details: Model Building
Output model

PDB-9pc9:
Structure of Synaptic Vesicle Protein 2A Bound to UCB7361

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