Molecular insights into anticonvulsant and botulinum neurotoxin binding of synaptic vesicle glycoprotein 2

Synaptic vesicle glycoprotein 2 (SV2) isoforms are crucial for synaptic function and neurotransmission. Although their precise physiological roles remain unclear, SV2 proteins serve as receptors for several botulinum neurotoxins (BoNTs) and are also the targets of anticonvulsants. Recent cryo-electron microscopy (cryo-EM) studies have greatly advanced our understanding of the structure and function of both SV2 proteins and BoNTs. The findings unveiled the molecular architectures of BoNTs, their receptors SV2A and SV2B, and how anticonvulsants bind to SV2A and how these interactions can be modulated allosterically. Additionally, the studies revealed a conserved binding mode in the interaction between BoNT/A and SV2 proteins, which involves significant conformational changes in the toxin. In this review, we will discuss these findings and their implications.