Yao, GuoruiZhang, SicaiMahrhold, StefanLam, Kwok-hoStern, DanielBagramyan, KarinePerry, KayKalkum, MarkusRummel, AndreasDong, MinJin, Rongsheng2017-01-032016Yao, G., S. Zhang, S. Mahrhold, K. Lam, D. Stern, K. Bagramyan, K. Perry, et al. 2016. “N-linked glycosylation of SV2 is required for binding and uptake of botulinum neurotoxin A.” Nature structural & molecular biology 23 (7): 656-662. doi:10.1038/nsmb.3245. http://dx.doi.org/10.1038/nsmb.3245.1545-9993http://nrs.harvard.edu/urn-3:HUL.InstRepos:29739089Botulinum neurotoxin serotype A1 (BoNT/A1) is one of the most dangerous potential bioterrorism agents, and exerts its action by invading motoneurons. It is also a licensed drug widely used for medical and cosmetic applications. Here we report a 2.0 Å resolution crystal structure of BoNT/A1 receptor-binding domain in complex with its neuronal receptor, the glycosylated human SV2C. We find that the neuronal tropism of BoNT/A1 requires recognition of both the peptide moiety and an N-linked glycan on SV2. This N-glycan—conserved in all SV2 isoforms across vertebrates—is essential for BoNT/A1 binding to neurons and its potent neurotoxicity. The glycan-binding interface on SV2 is targeted by a human BoNT/A1-neutralizing antibody currently licensed as an anti-botulism drug. Our studies reveal a new paradigm of host-pathogen interactions, in which pathogens exploit conserved host post-translational modifications to achieve highly specific receptor binding while also tolerating genetic changes across multiple isoforms of receptors.en-USJournal Article2017-01-0310.1038/nsmb.3245