Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
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Journal
IF	>30 >20 >10 >5 all

Title	Structural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A.
Journal, issue, pages	Nat Commun, Vol. 15, Issue 1, Page 3027, Year 2024
Publish date	Apr 18, 2024
Authors	Atsushi Yamagata / Kaori Ito / Takehiro Suzuki / Naoshi Dohmae / Tohru Terada / Mikako Shirouzu /
PubMed 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.
External links	Nat Commun / PubMed:38637505 / PubMed Central
Methods	EM (single particle)
Resolution	2.82 - 3.38 Å
Structure data	36392 8jlc EMDB-36392, PDB-8jlc: Cryo-EM structure of SV2A in complex with BoNT/A2 Hc and levetiracetam Method: EM (single particle) / Resolution: 2.88 Å 36394 8jle EMDB-36394, PDB-8jle: Cryo-EM structure of SV2A LD4 in complex with BoNT/A2 Hc in the SV2A-levetiracetam-BoNT/A2 Hc complex Method: EM (single particle) / Resolution: 2.82 Å 36395 8jlf EMDB-36395, PDB-8jlf: Cryo-EM structure of SV2A in complex with BoNT/A2 Hc Method: EM (single particle) / Resolution: 3.01 Å 36396 8jlg EMDB-36396, PDB-8jlg: Cryo-EM structure of SV2A in complex with BoNT/A2 Hc Method: EM (single particle) / Resolution: 2.87 Å 36397 8jlh EMDB-36397, PDB-8jlh: Cryo-EM structure of SV2A dimer in complex with BoNT/A2 Hc and levetiracetam Method: EM (single particle) / Resolution: 2.9 Å 36398 8jli EMDB-36398, PDB-8jli: Cryo-EM structure of SV2A dimer in complex levetiracetam Method: EM (single particle) / Resolution: 3.38 Å 36616 8js8 EMDB-36616, PDB-8js8: Cryo-EM structure of SV2A in complex with BoNT/A2 Hc and levetiracetam Method: EM (single particle) / Resolution: 2.88 Å 36617 8js9 EMDB-36617, PDB-8js9: Cryo-EM structure of SV2A in complex with BoNT/A2 Hc Method: EM (single particle) / Resolution: 3.01 Å EMDB-36933: Cryo-EM map of SV2A in complex with brivaracetam and BoNT/A2 Hc Method: EM (single particle) / Resolution: 3.11 Å EMDB-36934: Local map of SV2A LD4-BoNT/A2 Hc from SV2A-BoNT/A2 Hc-brivaracetam complex Method: EM (single particle) / Resolution: 3.07 Å 36935 8k77 EMDB-36935, PDB-8k77: Cryo-EM structure of SV2A in complex with BoNT/A2 Hc and brivaracetam Method: EM (single particle) / Resolution: 3.11 Å
Chemicals	ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose ChemComp, No image ChemComp-UKX: Unknown entry ChemComp, No image ChemComp-VLX: Unknown entry
Source	homo sapiens (human) clostridium botulinum (bacteria)
Keywords	TRANSPORT PROTEIN / Synaptic vesicle / epilepsy / MEMBRANE PROTEIN / botulinum neurotoxin / Synapse / antiepileptic drug