A Comprehensive Structural Analysis of Clostridium botulinum Neurotoxin A Cell-Binding Domain from Different Subtypes

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Abstract

Botulinum neurotoxins (BoNTs) cause flaccid neuromuscular paralysis by cleaving one of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex proteins. BoNTs display high affinity and specificity for neuromuscular junctions, making them one of the most potent neurotoxins known to date. There are seven serologically distinct BoNTs (serotypes BoNT/A to BoNT/G) which can be further divided into subtypes (e.g., BoNT/A1, BoNT/A2…) based on small changes in their amino acid sequence. Of these, BoNT/A1 and BoNT/B1 have been utilised to treat various diseases associated with spasticity and hypersecretion. There are potentially many more BoNT variants with differing toxicological profiles that may display other therapeutic benefits. This review is focused on the structural analysis of the cell-binding domain from BoNT/A1 to BoNT/A6 subtypes (HC/A1 to HC/A6), including features such as a ganglioside binding site (GBS), a dynamic loop, a synaptic vesicle glycoprotein 2 (SV2) binding site, a possible Lys–Cys/Cys–Cys bridge, and a hinge motion between the HCN and HCC subdomains. Characterising structural features across subtypes provides a better understanding of how the cell-binding domain functions and may aid the development of novel therapeutics.
Original languageEnglish
Article number92
Number of pages23
JournalToxins
Volume15
Issue number2
DOIs
Publication statusPublished - 18 Jan 2023

Funding

K.S.G. is supported by a joint postgraduate studentship between the University of Bath and Ipsen Bioinnovation Limited.

FundersFunder number
University of Bath and Ipsen Bioinnovation Limited

    Keywords

    • botulinum neurotoxin
    • cell-binding domain
    • ganglioside binding
    • structural analysis
    • synaptic vesicle glycoprotein 2

    ASJC Scopus subject areas

    • Health, Toxicology and Mutagenesis
    • Toxicology

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