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Open data
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Basic information
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Title | Cryo-EM structure of SV2A in complex with BoNT/A2 Hc | |||||||||
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Function / homology | ![]() regulation of gamma-aminobutyric acid secretion / 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) / synaptic vesicle priming / presynaptic active zone / transmembrane transporter activity / protein transmembrane transporter activity / GABA-ergic synapse ...regulation of gamma-aminobutyric acid secretion / 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) / synaptic vesicle priming / presynaptic active zone / transmembrane transporter activity / protein transmembrane transporter activity / GABA-ergic synapse / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | |||||||||
Biological species | ![]() ![]() ![]() ![]() ![]() | |||||||||
Method | ![]() ![]() | |||||||||
![]() | Yamagata A | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Structural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A. Authors: Atsushi Yamagata / Kaori Ito / Takehiro Suzuki / Naoshi Dohmae / Tohru Terada / Mikako Shirouzu / ![]() Abstract: More than one percent of people have epilepsy worldwide. Levetiracetam (LEV) is a successful new-generation antiepileptic drug (AED), and its derivative, brivaracetam (BRV), shows improved efficacy. ...More than one percent of people have epilepsy worldwide. Levetiracetam (LEV) is a successful new-generation antiepileptic drug (AED), and its derivative, brivaracetam (BRV), shows improved efficacy. Synaptic vesicle glycoprotein 2a (SV2A), a putative membrane transporter in the synaptic vesicles (SVs), has been identified as a target of LEV and BRV. SV2A also serves as a receptor for botulinum neurotoxin (BoNT), which is the most toxic protein and has paradoxically emerged as a potent reagent for therapeutic and cosmetic applications. Nevertheless, no structural analysis on AEDs and BoNT recognition by full-length SV2A has been available. Here we describe the cryo-electron microscopy structures of the full-length SV2A in complex with the BoNT receptor-binding domain, BoNT/A2 H and either LEV or BRV. The large fourth luminal domain of SV2A binds to BoNT/A2 H through protein-protein and protein-glycan interactions. LEV and BRV occupy the putative substrate-binding site in an outward-open conformation. A propyl group in BRV creates additional contacts with SV2A, explaining its higher binding affinity than that of LEV, which was further supported by label-free spectral shift assay. Numerous LEV derivatives have been developed as AEDs and positron emission tomography (PET) tracers for neuroimaging. Our work provides a structural framework for AEDs and BoNT recognition of SV2A and a blueprint for the rational design of additional AEDs and PET tracers. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 97 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 16.2 KB 16.2 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 9.9 KB | Display | ![]() |
Images | ![]() | 33.8 KB | ||
Masks | ![]() | 103 MB | ![]() | |
Filedesc metadata | ![]() | 6 KB | ||
Others | ![]() ![]() | 95.7 MB 95.7 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8jlgMC ![]() 8jlcC ![]() 8jleC ![]() 8jlfC ![]() 8jlhC ![]() 8jliC ![]() 8js8C ![]() 8js9C ![]() 8k77C M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.83 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
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-Half map: #2
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Density Histograms |
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Sample components
-Entire : SV2A LD4 in complex with BoNT/A2 Hc domain from the SV2A-BoNT/A2 ...
Entire | Name: SV2A LD4 in complex with BoNT/A2 Hc domain from the SV2A-BoNT/A2 Hc complex |
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Components |
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-Supramolecule #1: SV2A LD4 in complex with BoNT/A2 Hc domain from the SV2A-BoNT/A2 ...
Supramolecule | Name: SV2A LD4 in complex with BoNT/A2 Hc domain from the SV2A-BoNT/A2 Hc complex type: complex / ID: 1 / Parent: 0 / Macromolecule list: #2 |
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Source (natural) | Organism: ![]() ![]() |
-Macromolecule #1: Synaptic vesicle glycoprotein 2A
Macromolecule | Name: Synaptic vesicle glycoprotein 2A / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 13.056498 KDa |
Recombinant expression | Organism: ![]() ![]() ![]() |
Sequence | String: YASRTKVFPG ERVEHVTFNF TLENQIHRGG QYFNDKFIGL RLKSVSFEDS LFEECYFEDV TSSNTFFRNC TFINTVFYNT DLFEYKFVN SRLINSTFLH NKEGCPLDVT GT UniProtKB: Synaptic vesicle glycoprotein 2A |
-Macromolecule #2: Botulinum neurotoxin
Macromolecule | Name: Botulinum neurotoxin / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() ![]() |
Molecular weight | Theoretical: 49.456191 KDa |
Recombinant expression | Organism: ![]() ![]() ![]() |
Sequence | String: KNIVNTSILS IVYKKDDLID LSRYGAKINI GDRVYYDSID KNQIKLINLE SSTIEVILKN AIVYNSMYEN FSTSFWIKIP KYFSKINLN NEYTIINCIE NNSGWKVSLN YGEIIWTLQD NKQNIQRVVF KYSQMVNISD YINRWIFVTI TNNRLTKSKI Y INGRLIDQ ...String: KNIVNTSILS IVYKKDDLID LSRYGAKINI GDRVYYDSID KNQIKLINLE SSTIEVILKN AIVYNSMYEN FSTSFWIKIP KYFSKINLN NEYTIINCIE NNSGWKVSLN YGEIIWTLQD NKQNIQRVVF KYSQMVNISD YINRWIFVTI TNNRLTKSKI Y INGRLIDQ KPISNLGNIH ASNKIMFKLD GCRDPRRYIM IKYFNLFDKE LNEKEIKDLY DSQSNSGILK DFWGNYLQYD KP YYMLNLF DPNKYVDVNN IGIRGYMYLK GPRGSVVTTN IYLNSTLYEG TKFIIKKYAS GNEDNIVRNN DRVYINVVVK NKE YRLATN ASQAGVEKIL SALEIPDVGN LSQVVVMKSK DDQGIRNKCK MNLQDNNGND IGFIGFHLYD NIAKLVASNW YNRQ VGKAS RTFGCSWEFI PVDDGWGESS L UniProtKB: Botulinum neurotoxin |
-Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 2 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-Experimental details
-Structure determination
Method | ![]() |
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Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 Details: 20 mM Hepes (pH7.5), 150 mM NaCl, 0.001% LMNG, 0.0002% cholesterol hemisuccinate |
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Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 297 K / Instrument: FEI VITROBOT MARK IV |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD![]() |
Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Number real images: 4890 / Average electron dose: 50.0 e/Å2 |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |