8JS8

Cryo-EM structure of SV2A in complex with BoNT/A2 Hc and levetiracetam

Summary for 8JS8

• Entry DOI: 10.2210/pdb8js8/pdb
• EMDB information: 36616
• Descriptor: Synaptic vesicle glycoprotein 2A, Botulinum neurotoxin, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: synaptic vesicle, epilepsy, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 134413.37

Authors

Yamagata, A. (deposition date: 2023-06-19, release date: 2024-05-01, Last modification date: 2024-10-16)

Primary citation

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, 15:3027-3027, 2024

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. 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.

PubMed: 38637505
DOI: 10.1038/s41467-024-47322-4

Experimental method

ELECTRON MICROSCOPY (2.88 Å)