Yao, GuoruiLam, Kwok-hoWeisemann, JasminPeng, LishengKrez, NadjaPerry, KayShoemaker, Charles B.Dong, MinRummel, AndreasJin, Rongsheng2017-11-212017Yao, Guorui, Kwok-ho Lam, Jasmin Weisemann, Lisheng Peng, Nadja Krez, Kay Perry, Charles B. Shoemaker, Min Dong, Andreas Rummel, and Rongsheng Jin. 2017. “A camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding.” Scientific Reports 7 (1): 7438. doi:10.1038/s41598-017-07457-5. http://dx.doi.org/10.1038/s41598-017-07457-5.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34375035Antibody treatment is currently the only available countermeasure for botulism, a fatal illness caused by flaccid paralysis of muscles due to botulinum neurotoxin (BoNT) intoxication. Among the seven major serotypes of BoNT/A-G, BoNT/A poses the most serious threat to humans because of its high potency and long duration of action. Prior to entering neurons and blocking neurotransmitter release, BoNT/A recognizes motoneurons via a dual-receptor binding process in which it engages both the neuron surface polysialoganglioside (PSG) and synaptic vesicle glycoprotein 2 (SV2). Previously, we identified a potent neutralizing antitoxin against BoNT/A1 termed ciA-C2, derived from a camelid heavy-chain-only antibody (VHH). In this study, we demonstrate that ciA-C2 prevents BoNT/A1 intoxication by inhibiting its binding to neuronal receptor SV2. Furthermore, we determined the crystal structure of ciA-C2 in complex with the receptor-binding domain of BoNT/A1 (HCA1) at 1.68 Å resolution. The structure revealed that ciA-C2 partially occupies the SV2-binding site on HCA1, causing direct interference of HCA1 interaction with both the N-glycan and peptide-moiety of SV2. Interestingly, this neutralization mechanism is similar to that of a monoclonal antibody in clinical trials, despite that ciA-C2 is more than 10-times smaller. Taken together, these results enlighten our understanding of BoNT/A1 interactions with its neuronal receptor, and further demonstrate that inhibiting toxin binding to the host receptor is an efficient countermeasure strategy.en-USJournal Article2017-11-2110.1038/s41598-017-07457-5