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Structural and Biochemical Characterization of Botulinum Neurotoxin Subtype B2 Binding to Its Receptors
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- Davies, Jonathan R. (author)
- Stockholm University,Stockholms universitet,Institutionen för biokemi och biofysik
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- Masuyer, Geoffrey (author)
- Stockholm University,Stockholms universitet,Institutionen för biokemi och biofysik,University of Bath, United Kingdom
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- Stenmark, Pål (author)
- Stockholm University,Lunds universitet,Stockholms universitet,Institutionen för biokemi och biofysik,Lund University, Sweden,Strukturell biokemi,Forskargrupper vid Lunds universitet,Structural Biochemistry,Lund University Research Groups
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(creator_code:org_t)
- 2020-09-17
- English.
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In: Toxins. - : MDPI AG. - 2072-6651. ; 12:9
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Abstract
Subject headings
Close
- 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.
Subject headings
- NATURVETENSKAP -- Biologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Keyword
- Clostridium botulinum
- botulism
- botulinum neurotoxin
- BoNT
- B
- synaptotagmin
- ganglioside
Publication and Content Type
- ref (subject category)
- art (subject category)
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