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Open AccessArticle

Structural and Biochemical Characterization of Botulinum Neurotoxin Subtype B2 Binding to Its Receptors

1
Department of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, Sweden
2
Department of Pharmacy and Pharmacology, Centre for Therapeutic Innovation, University of Bath, Bath BA2 7AY, UK
3
Department of Experimental Medical Science, Lund University, SE-221 00 Lund, Sweden
*
Authors to whom correspondence should be addressed.
Toxins 2020, 12(9), 603; https://doi.org/10.3390/toxins12090603
Received: 31 July 2020 / Revised: 14 September 2020 / Accepted: 16 September 2020 / Published: 17 September 2020
Botulinum neurotoxins (BoNTs) can be used therapeutically to treat a wide range of neuromuscular and neurological conditions. A collection of natural BoNT variants exists which can be classified into serologically distinct serotypes (BoNT/B), and further divided into subtypes (BoNT/B1, B2, …). BoNT subtypes share a high degree of sequence identity within the same serotype yet can display large variation in toxicity. One such example is BoNT/B2, which was isolated from Clostridium botulinum strain 111 in a clinical case of botulism, and presents a 10-fold lower toxicity than BoNT/B1. In an effort to understand the molecular mechanisms behind this difference in potency, we here present the crystal structures of BoNT/B2 in complex with the ganglioside receptor GD1a, and with the human synaptotagmin I protein receptor. We show, using receptor-binding assays, that BoNT/B2 has a slightly higher affinity for GD1a than BoNT/B1, and confirm its considerably weaker affinity for its protein receptors. Although the overall receptor-binding mechanism is conserved for both receptors, structural analysis suggests the lower affinity of BoNT/B2 is the result of key substitutions, where hydrophobic interactions important for synaptotagmin-binding are replaced by polar residues. This study provides a template to drive the development of future BoNT therapeutic molecules centered on assessing the natural subtype variations in receptor-binding that appears to be one of the principal stages driving toxicity. View Full-Text
Keywords: Clostridium botulinum; botulism; botulinum neurotoxin; BoNT/B; synaptotagmin; ganglioside Clostridium botulinum; botulism; botulinum neurotoxin; BoNT/B; synaptotagmin; ganglioside
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Davies, J.R.; Masuyer, G.; Stenmark, P. Structural and Biochemical Characterization of Botulinum Neurotoxin Subtype B2 Binding to Its Receptors. Toxins 2020, 12, 603.

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