A team of researchers from the University of California, Irvine, have revealed the first crystal structures of the receptor-binding domain of botulinum neurotoxin E (BoNT/E) in complex with its human neuronal receptors, synaptic vesicle glycoprotein 2A (SV2A). This structure and other findings in the new study could be harnessed to engineer new BoNT/E variants with modified specificities toward different SV2 isoforms for new clinical developments.