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- PDB-8uo8: Structure of synaptic vesicle protein 2B with padsevonil -

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Basic information

Entry
Database: PDB / ID: 8uo8
TitleStructure of synaptic vesicle protein 2B with padsevonil
ComponentsSynaptic vesicle glycoprotein 2B
KeywordsTRANSPORT PROTEIN / Synaptic vesicle / SLC22 / Inhibitor / Antiepileptic
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) / regulation of presynaptic cytosolic calcium ion concentration / neurotransmitter transport / regulation of synaptic vesicle exocytosis / transmembrane transporter activity / acrosomal vesicle / synaptic vesicle membrane ...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) / regulation of presynaptic cytosolic calcium ion concentration / neurotransmitter transport / regulation of synaptic vesicle exocytosis / transmembrane transporter activity / acrosomal vesicle / synaptic vesicle membrane / synaptic vesicle / chemical synaptic transmission / membrane / plasma membrane
Similarity search - Function
Synaptic vesicle protein SV2 / Major facilitator, sugar transporter-like / Sugar (and other) transporter / Sugar transporter, conserved site / Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
Chem-43Y / 1,2-DIDECANOYL-SN-GLYCERO-3-[PHOSPHO-L-SERINE] / : / CHOLESTEROL HEMISUCCINATE / Synaptic vesicle glycoprotein 2B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsMartin, M.F. / Mittal, A. / Levin, E. / Adams, C. / Yang, M. / Ledecq, M. / Horanyi, P.S. / Coleman, J.A.
Funding support United States, 1items
OrganizationGrant numberCountry
Brain & Behavior Research Foundation30153 United States
CitationJournal: Nat Struct Mol Biol / Year: 2024
Title: Structures of synaptic vesicle protein 2A and 2B bound to anticonvulsants.
Authors: Anshumali Mittal / Matthew F Martin / Elena J Levin / Christopher Adams / Meng Yang / Laurent Provins / Adrian Hall / Martin Procter / Marie Ledecq / Alexander Hillisch / Christian Wolff / ...Authors: Anshumali Mittal / Matthew F Martin / Elena J Levin / Christopher Adams / Meng Yang / Laurent Provins / Adrian Hall / Martin Procter / Marie Ledecq / Alexander Hillisch / Christian Wolff / Michel Gillard / Peter S Horanyi / Jonathan A Coleman /
Abstract: Epilepsy is a common neurological disorder characterized by abnormal activity of neuronal networks, leading to seizures. The racetam class of anti-seizure medications bind specifically to a membrane ...Epilepsy is a common neurological disorder characterized by abnormal activity of neuronal networks, leading to seizures. The racetam class of anti-seizure medications bind specifically to a membrane protein found in the synaptic vesicles of neurons called synaptic vesicle protein 2 (SV2) A (SV2A). SV2A belongs to an orphan subfamily of the solute carrier 22 organic ion transporter family that also includes SV2B and SV2C. The molecular basis for how anti-seizure medications act on SV2s remains unknown. Here we report cryo-electron microscopy structures of SV2A and SV2B captured in a luminal-occluded conformation complexed with anticonvulsant ligands. The conformation bound by anticonvulsants resembles an inhibited transporter with closed luminal and intracellular gates. Anticonvulsants bind to a highly conserved central site in SV2s. These structures provide blueprints for future drug design and will facilitate future investigations into the biological function of SV2s.
History
DepositionOct 19, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 22, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 26, 2024Group: Data collection / Database references / Structure summary
Category: audit_author / citation ...audit_author / citation / citation_author / em_admin / em_author_list
Item: _audit_author.name / _citation.country ..._audit_author.name / _citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update / _em_author_list.author
Revision 1.2Oct 23, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Synaptic vesicle glycoprotein 2B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,12510
Polymers77,5151
Non-polymers3,6109
Water905
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

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Protein / Sugars , 2 types, 4 molecules A

#1: Protein Synaptic vesicle glycoprotein 2B


Mass: 77515.016 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SV2B / Cell line (production host): tSA201 / Production host: Homo sapiens (human) / References: UniProt: Q7L1I2
#2: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 6 types, 11 molecules

#3: Chemical ChemComp-X3U / (4R)-4-(2-chloro-2,2-difluoroethyl)-1-{[(4R)-2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one


Mass: 432.797 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H14ClF5N4O2S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-PS1 / 1,2-DIDECANOYL-SN-GLYCERO-3-[PHOSPHO-L-SERINE]


Mass: 566.642 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H49NO10P
#5: Chemical ChemComp-9Z9 / (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en


Mass: 544.805 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H56O5 / Comment: detergent*YM
#6: Chemical ChemComp-43Y / [(2R)-3-[oxidanyl-[2-(trimethyl-$l^{4}-azanyl)ethoxy]phosphoryl]oxy-2-propanoyloxy-propyl] propanoate / 1,2-dipropionyl-sn-glycero-3-phosphocholine


Mass: 370.356 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H29NO8P
#7: Chemical ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H50O4
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: SV2B complexed with padsevonil / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 77.4 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
Details: 150 mM NaCl, 20 mM Tris pH 8.0, .4 mM glyco-diosgenin, 1 uM padsevonil
SpecimenConc.: 4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R2/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE-PROPANE / 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: 1500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 60 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
IDNameCategory
2EPUimage acquisition
7Cootmodel fitting
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 62528 / Symmetry type: POINT
Atomic model buildingAccession code: AF-Q7L1I2-F1 / Source name: AlphaFold / Type: in silico model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0039656
ELECTRON MICROSCOPYf_angle_d0.53317435
ELECTRON MICROSCOPYf_dihedral_angle_d9.2653812
ELECTRON MICROSCOPYf_chiral_restr0.039739
ELECTRON MICROSCOPYf_plane_restr0.0021360

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