5L21

A camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding.

(2017) Sci Rep 7: 7438-7438

• PubMed: 28785006 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1038/s41598-017-07457-5
• Primary Citation of Related Structures:  
  5L21


• PubMed Abstract: 
  

  Antibody 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 (H _C A1) at 1.68 Å resolution. The structure revealed that ciA-C2 partially occupies the SV2-binding site on H _C A1, causing direct interference of H _C 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.

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Organizational Affiliation: 

Department of Physiology and Biophysics, University of California, Irvine, California, USA.