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- EMDB-70564: Cryo-EM structure of human SV2A in complex with UCBJ -

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Basic information

Entry
Database: EMDB / ID: EMD-70564
TitleCryo-EM structure of human SV2A in complex with UCBJ
Map data
Sample
  • Complex: Human SV2A in complex with UCBJ
    • Protein or peptide: Synaptic vesicle glycoprotein 2A
  • Ligand: (4R)-1-[(3-methylpyridin-4-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one
KeywordsSLC transporter / SLC22 family / MEMBRANE PROTEIN / ligand binding
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.39 Å
AuthorsPidathala S / Dai Y / Lee CH
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM143282 United States
CitationJournal: Nat Commun / Year: 2025
Title: Structural pharmacology of SV2A reveals an allosteric modulation mechanism in the major facilitator superfamily.
Authors: Shabareesh Pidathala / Xiao Chen / Yaxin Dai / Long N Nguyen / Christoph Gorgulla / Yiming Niu / Fangyu Liu / Chia-Hsueh Lee /
Abstract: The synaptic vesicle glycoprotein 2A (SV2A), a member of the major facilitator superfamily (MFS), is a key target for antiseizure medications and a biomarker for synaptic density imaging. Despite its ...The synaptic vesicle glycoprotein 2A (SV2A), a member of the major facilitator superfamily (MFS), is a key target for antiseizure medications and a biomarker for synaptic density imaging. Despite its clinical importance, the mechanisms underlying SV2A ligand binding and modulation remain poorly understood. Here, we report sub-3 Å resolution cryo-electron microscopy (cryo-EM) structures of human SV2A in its apo form and in complex with FDA-approved antiseizure medication levetiracetam; PET imaging tracer UCB-J; experimental antiseizure drug padsevonil; and allosteric modulator UCB1244283. We find that levetiracetam and UCB-J induce vestibule occlusion, a hallmark conformational transition of MFS transporters that had not been observed in previous SV2A structures. UCB1244283 binds to an allosteric site and enhances orthosteric ligand engagement by stabilizing the occluded state and slowing ligand dissociation. Notably, padsevonil occupies both orthosteric and allosteric sites, functionally precluding modulation. These findings uncover an allosteric mechanism of regulation and provide a structural framework for the development of modulators targeting SV2A and related MFS transporters.
History
DepositionMay 9, 2025-
Header (metadata) releaseDec 10, 2025-
Map releaseDec 10, 2025-
UpdateDec 10, 2025-
Current statusDec 10, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70564.png

Downloads & links

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Map

FileDownload / File: emd_70564.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 384 pix.
= 249.216 Å		0.65 Å/pix.
x 384 pix.
= 249.216 Å		0.65 Å/pix.
x 384 pix.
= 249.216 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.649 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.197
Minimum - Maximum-1.0066261 - 1.6117786
Average (Standard dev.)0.00051173015 (±0.03278444)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 249.216 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_70564_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_70564_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : Human SV2A in complex with UCBJ

EntireName: Human SV2A in complex with UCBJ
Components
  • Complex: Human SV2A in complex with UCBJ
    • Protein or peptide: Synaptic vesicle glycoprotein 2A
  • Ligand: (4R)-1-[(3-methylpyridin-4-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one

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Supramolecule #1: Human SV2A in complex with UCBJ

SupramoleculeName: Human SV2A in complex with UCBJ / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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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: 67.822164 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: AQRRKEREEL AQQYEAILRE CGHGRFQWTL YFVLGLALMA DGVEVFVVGF VLPSAEKDMC LSDSNKGMLG LIVYLGMMVG AFLWGGLAD RLGRRQCLLI SLSVNSVFAF FSSFVQGYGT FLFCRLLSGV GIGGSIPIVF SYFSEFLAQE KRGEHLSWLC M FWMIGGVY ...String:
AQRRKEREEL AQQYEAILRE CGHGRFQWTL YFVLGLALMA DGVEVFVVGF VLPSAEKDMC LSDSNKGMLG LIVYLGMMVG AFLWGGLAD RLGRRQCLLI SLSVNSVFAF FSSFVQGYGT FLFCRLLSGV GIGGSIPIVF SYFSEFLAQE KRGEHLSWLC M FWMIGGVY AAAMAWAIIP HYGWSFQMGS AYQFHSWRVF VLVCAFPSVF AIGALTTQPE SPRFFLENGK HDEAWMVLKQ VH DTNMRAK GHPERVFSVT HIKTIHQEDE LIEIQSDTGT WYQRWGVRAL SLGGQVWGNF LSCFGPEYRR ITLMMMGVWF TMS FSYYGL TVWFPDMIRH LQAVDYASRT KVFPGERVEH VTFNFTLENQ IHRGGQYFND KFIGLRLKSV SFEDSLFEEC YFED VTSSN TFFRNCTFIN TVFYNTDLFE YKFVNSRLIN STFLHNKEGC PLDVTGTGEG AYMVYFVSFL GTLAVLPGNI VSALL MDKI GRLRMLAGSS VMSCVSCFFL SFGNSESAMI ALLCLFGGVS IASWNALDVL TVELYPSDKR TTAFGFLNAL CKLAAV LGI SIFTSFVGIT KAAPILFASA ALALGSSLAL KLPETRGQVL Q

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Macromolecule #2: (4R)-1-[(3-methylpyridin-4-yl)methyl]-4-(3,4,5-trifluorophenyl)py...

MacromoleculeName: (4R)-1-[(3-methylpyridin-4-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one
type: ligand / ID: 2 / Number of copies: 1 / Formula: A1CCA
Molecular weightTheoretical: 320.309 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

BufferpH: 7
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.1 µm / Nominal defocus min: 1.1 µm
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: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.39 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 304664
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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