Structural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A

• Published in: Nature Communications Vol. 15; no. 1; pp. 3027 - 13
• Main Authors: Yamagata, Atsushi, Ito, Kaori, Suzuki, Takehiro, Dohmae, Naoshi, Terada, Tohru, Shirouzu, Mikako
• Format: Journal Article
• Language: English
• Published: London Springer Science and Business Media LLC 18.04.2024; Nature Publishing Group UK; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 631/378/1689/178; 631/535/1258/1259; 692/617/375/178; 82/58; 82/80; 82/83; Affinity; Antiepileptic agents; Binding sites; Botulinum toxin; Drugs; Electron microscopy; Epilepsy; Etiracetam; Glycan; Glycoproteins; Humanities and Social Sciences; Medical imaging; multidisciplinary; Neuroimaging; Neurotoxins; Positron emission; Positron emission tomography; Proteins; Q; Reagents; Receptors; Recognition; Science; Science (multidisciplinary); Structural analysis; Substrates; Synaptic vesicles; Toxins; Tracers
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-47322-4

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 C, and either LEV or BRV. The large fourth luminal domain of SV2A binds to BoNT/A2 H C 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. SV2A is a receptor for botulinum neurotoxin (BoNT) and new generation antiepileptic drugs (AEDs). Here the authors report cryo-EM structures of SV2A in complex with BoNT receptor binding domain and AEDs highlighting the difference in the binding affinity between AEDs.