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- PDB-9ntc: Structure of Synaptic Vesicle Protein 2A Bound to Brivaracetam an... -

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Basic information

Entry
Database: PDB / ID: 9ntc
TitleStructure of Synaptic Vesicle Protein 2A Bound to Brivaracetam and UCB1244283
ComponentsSynaptic vesicle glycoprotein 2A
KeywordsMEMBRANE PROTEIN / Synaptic vesicle / SLC22 / Inhibitor / Positive allosteric modulator
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
: / : / CHOLESTEROL / : / Synaptic vesicle glycoprotein 2A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.05 Å
AuthorsMittal, A. / Martin, M.F. / Ledecq, M. / Horanyi, P.S. / Coleman, J.A.
Funding support United States, 1items
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
DepositionMar 18, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 10, 2025Provider: repository / Type: Initial release
Revision 1.0Sep 10, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
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Revision 1.0Sep 10, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
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Revision 1.0Sep 10, 2025Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Sep 10, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Synaptic vesicle glycoprotein 2A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,5415
Polymers76,3191
Non-polymers1,2224
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Synaptic vesicle glycoprotein 2A


Mass: 76319.047 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SV2A, KIAA0736, PSEC0174 / Cell line (production host): tsA201 / Production host: Homo sapiens (human) / References: UniProt: Q7L0J3
#2: Chemical ChemComp-A1B1J / (3R)-4-(3,5-dimethylphenyl)-N-(2-methoxyphenyl)-3-methylbutanamide


Mass: 311.418 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H25NO2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-VLX / (2S)-2-[(4R)-2-oxidanylidene-4-propyl-pyrrolidin-1-yl]butanamide


Mass: 212.289 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H20N2O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O
#5: Chemical ChemComp-A1B1I / (3S)-4-(3,5-dimethylphenyl)-N-(2-methoxyphenyl)-3-methylbutanamide


Mass: 311.418 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H25NO2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: SV2A bound to brivaracetam and UCB1244283 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 75.5 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Strain: tsa201
Buffer solutionpH: 8
SpecimenConc.: 8.13 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid mesh size: 200 divisions/in. / Grid type: Quantifoil R2/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 298 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 194000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k)
EM imaging opticsEnergyfilter name: TFS Selectris / Energyfilter slit width: 10 eV

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Processing

EM software
IDNameVersionCategoryDetails
7Coot0.9.8.95 ELmodel fitting
13PHENIX1.20.1-4487model refinementReal Space refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.05 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 36477 / Symmetry type: POINT
Atomic model buildingPDB-ID: 8UO9

8uo9


Pdb chain-ID: A / Accession code: 8UO9 / Chain residue range: 144-738 / Details: PDB 8UO9 was used for building initial model. / Pdb chain residue range: 144-738 / Source name: PDB / Type: experimental model
RefinementHighest resolution: 3.05 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0063409
ELECTRON MICROSCOPYf_angle_d0.5984620
ELECTRON MICROSCOPYf_dihedral_angle_d10.245473
ELECTRON MICROSCOPYf_chiral_restr0.038516
ELECTRON MICROSCOPYf_plane_restr0.005566

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