PXD050355

PXD050355 is an original dataset announced via ProteomeXchange.

Title	Structural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A
Description	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 (SV), 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 HC, and either LEV or BRV. The large fourth luminal domain of SV2A binds to BoNT/A2 HC 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 new AEDs and PET tracers.
HostingRepository	PRIDE
AnnounceDate	2024-06-23
AnnouncementXML	Submission_2024-06-23_01:17:36.506.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD050355
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Takehiro Suzuki
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetic acid derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2024-03-05 03:51:15	ID requested
⏵ 1	2024-06-23 01:17:37	announced

Yamagata A, Ito K, Suzuki T, Dohmae N, Terada T, Shirouzu M, Structural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A. Nat Commun, 15(1):3027(2024) [pubmed]

10.6019/PXD050355;

10.1038/s41467-024-47322-4;

submitter keyword: BoNT, LEV,SV2A, AED

Naoshi Dohmae
contact affiliation	Biomolecular characterization unit, Center for Sustainable Resource Science, RIKEN
contact email	dohmae@riken.jp
lab head
Takehiro Suzuki
contact affiliation	RIKEN Center for Sustainable Resource Science
contact email	takehirosuzuki@riken.jp
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD050355
     1. Label: PRIDE project
     2. Name: Structural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A