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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 (H<jats:sub>C<\/jats:sub>A1) at 1.68\u2009\u00c5 resolution. The structure revealed that ciA-C2 partially occupies the SV2-binding site on H<jats:sub>C<\/jats:sub>A1, causing direct interference of H<jats:sub>C<\/jats:sub>A1 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.<\/jats:p>","DOI":"10.1038\/s41598-017-07457-5","type":"journal-article","created":{"date-parts":[[2017,8,1]],"date-time":"2017-08-01T13:42:35Z","timestamp":1501594955000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["A camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding"],"prefix":"10.1038","volume":"7","author":[{"given":"Guorui","family":"Yao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwok-ho","family":"Lam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmin","family":"Weisemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisheng","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadja","family":"Krez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kay","family":"Perry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9738-1361","authenticated-orcid":false,"given":"Charles B.","family":"Shoemaker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0645-1641","authenticated-orcid":false,"given":"Andreas","family":"Rummel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0348-7363","authenticated-orcid":false,"given":"Rongsheng","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,8,7]]},"reference":[{"key":"7457_CR1","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1001\/jama.285.8.1059","volume":"285","author":"SS Arnon","year":"2001","unstructured":"Arnon, S. 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