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Structural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A

Author

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  • Atsushi Yamagata

    (RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku)

  • Kaori Ito

    (RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku)

  • Takehiro Suzuki

    (RIKEN Center for Sustainable Resource Science)

  • Naoshi Dohmae

    (RIKEN Center for Sustainable Resource Science)

  • Tohru Terada

    (Graduate School of Agricultural and Life Sciences, The University of Tokyo)

  • Mikako Shirouzu

    (RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku)

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 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 additional AEDs and PET tracers.

Suggested Citation

  • Atsushi Yamagata & Kaori Ito & Takehiro Suzuki & Naoshi Dohmae & Tohru Terada & Mikako Shirouzu, 2024. "Structural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47322-4
    DOI: 10.1038/s41467-024-47322-4
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    References listed on IDEAS

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    1. Katrin I. Willig & Silvio O. Rizzoli & Volker Westphal & Reinhard Jahn & Stefan W. Hell, 2006. "STED microscopy reveals that synaptotagmin remains clustered after synaptic vesicle exocytosis," Nature, Nature, vol. 440(7086), pages 935-939, April.
    2. Roger M. Benoit & Daniel Frey & Manuel Hilbert & Josta T. Kevenaar & Mara M. Wieser & Christian U. Stirnimann & David McMillan & Tom Ceska & Florence Lebon & Rolf Jaussi & Michel O. Steinmetz & Gebhar, 2014. "Structural basis for recognition of synaptic vesicle protein 2C by botulinum neurotoxin A," Nature, Nature, vol. 505(7481), pages 108-111, January.
    3. Rongsheng Jin & Andreas Rummel & Thomas Binz & Axel T. Brunger, 2006. "Botulinum neurotoxin B recognizes its protein receptor with high affinity and specificity," Nature, Nature, vol. 444(7122), pages 1092-1095, December.
    4. Zheng Liu & Pyung-Gang Lee & Nadja Krez & Kwok-ho Lam & Hao Liu & Adina Przykopanski & Peng Chen & Guorui Yao & Sicai Zhang & Jacqueline M. Tremblay & Kay Perry & Charles B. Shoemaker & Andreas Rummel, 2023. "Structural basis for botulinum neurotoxin E recognition of synaptic vesicle protein 2," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Atsushi Yamagata & Yoshiko Murata & Kosuke Namba & Tohru Terada & Shuya Fukai & Mikako Shirouzu, 2022. "Uptake mechanism of iron-phytosiderophore from the soil based on the structure of yellow stripe transporter," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
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