The four-domain structure of botulinum neurotoxins (BoNTs) reflects their multistep intoxication process. The high toxicity of BoNTs primarily results from specific binding and uptake into neurons mediated by their 50-kDa cell-binding fragment (HC). X-ray crystallography data have revealed that the HCfragment consists of two domains of equal size, named the 25-kDa N-terminal half of HC(HCN) and the 25-kDa C-terminal half of HC(HCC).