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- EMDB-71502: Structure of Synaptic Vesicle Protein 2A Bound to Levetiracetam a... -

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Basic information

Entry
Database: EMDB / ID: EMD-71502
TitleStructure of Synaptic Vesicle Protein 2A Bound to Levetiracetam and UCB1244283
Map dataSharpened map
Sample
  • Complex: SV2A bound to levetiracetam and UCB1244283
    • Protein or peptide: Synaptic vesicle glycoprotein 2A
KeywordsSynaptic vesicle / SLC22 / Inhibitor / LEV / MEMBRANE PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.93 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_71502.png

Downloads & links

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Map

FileDownload / File: emd_71502.map.gz / Format: CCP4 / Size: 144.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map
Projections & slices

Image control

Size
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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

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.719 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.088
Minimum - Maximum-0.19918822 - 0.31361946
Average (Standard dev.)0.0009779984 (±0.012104508)
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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Additional map: Unsharpened map

Fileemd_71502_additional_1.map
AnnotationUnsharpened map
Projections & Slices
AxesZYX

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Half map: Half map A

Fileemd_71502_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 A

Fileemd_71502_half_map_2.map
AnnotationHalf map A
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Sample components

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Entire : SV2A bound to levetiracetam and UCB1244283

EntireName: SV2A bound to levetiracetam and UCB1244283
Components
  • Complex: SV2A bound to levetiracetam and UCB1244283
    • Protein or peptide: Synaptic vesicle glycoprotein 2A

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Supramolecule #1: SV2A bound to levetiracetam and UCB1244283

SupramoleculeName: SV2A bound to levetiracetam and UCB1244283 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
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 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGYYRGEGTQ DEEEGGASSD ATEGHDEDDE IYEGEYQGIP RAESGGKGER MADGAPLAGV RGGLSDGEGP PGGRGEAQRR KEREELAQQ YEAILRECGH GRFQWTLYFV LGLALMADGV EVFVVGFVLP SAEKDMCLSD SNKGMLGLIV YLGMMVGAFL W GGLADRLG ...String:
MGYYRGEGTQ DEEEGGASSD ATEGHDEDDE IYEGEYQGIP RAESGGKGER MADGAPLAGV RGGLSDGEGP PGGRGEAQRR KEREELAQQ YEAILRECGH GRFQWTLYFV LGLALMADGV EVFVVGFVLP SAEKDMCLSD SNKGMLGLIV YLGMMVGAFL W GGLADRLG RRQCLLISLS VNSVFAFFSS FVQGYGTFLF CRLLSGVGIG GSIPIVFSYF SEFLAQEKRG EHLSWLCMFW MI GGVYAAA MAWAIIPHYG WSFQMGSAYQ FHSWRVFVLV CAFPSVFAIG ALTTQPESPR FFLENGKHDE AWMVLKQVHD TNM RAKGHP ERVFSVTHIK TIHQEDELIE IQSDTGTWYQ RWGVRALSLG GQVWGNFLSC FGPEYRRITL MMMGVWFTMS FSYY GLTVW FPDMIRHLQA VDYASRTKVF PGERVEHVTF NFTLENQIHR GGQYFNDKFI GLRLKSVSFE DSLFEECYFE DVTSS NTFF RNCTFINTVF YNTDLFEYKF VNSRLINSTF LHNKEGCPLD VTGTGEGAYM VYFVSFLGTL AVLPGNIVSA LLMDKI GRL RMLAGSSVMS CVSCFFLSFG NSESAMIALL CLFGGVSIAS WNALDVLTVE LYPSDKRTTA FGFLNALCKL AAVLGIS IF TSFVGITKAA PILFASAALA LGSSLALKLP ETRGQVLQLE VLFQ

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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

Concentration5.3 mg/mL
BufferpH: 8
GridModel: Quantifoil R2/1 / Mesh: 200 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 298 K

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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: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 6.93 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 39638
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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