2018
DOI: 10.3390/toxins10100421
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Variations in the Botulinum Neurotoxin Binding Domain and the Potential for Novel Therapeutics

Abstract: Botulinum neurotoxins (BoNTs) are categorised into immunologically distinct serotypes BoNT/A to /G). Each serotype can also be further divided into subtypes based on differences in amino acid sequence. BoNTs are ~150 kDa proteins comprised of three major functional domains: an N-terminal zinc metalloprotease light chain (LC), a translocation domain (HN), and a binding domain (HC). The HC is responsible for targeting the BoNT to the neuronal cell membrane, and each serotype has evolved to bind via different mec… Show more

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Cited by 26 publications
(25 citation statements)
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References 138 publications
(151 reference statements)
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“…Electron density was excellent throughout, with all H C /A5 residues (except the N-terminal 6xHis tag and Lys871) being easily observed. The structure closely resembles the structures of other BoNT-binding domains [6] with an N-terminal jelly roll-like fold and C-terminal modified b-trefoil fold containing a conserved ganglioside-binding site (SxWY) (Fig. 2).…”
Section: Structure Of the Bont/a5-binding Domain (H C /A5)supporting
confidence: 53%
See 1 more Smart Citation
“…Electron density was excellent throughout, with all H C /A5 residues (except the N-terminal 6xHis tag and Lys871) being easily observed. The structure closely resembles the structures of other BoNT-binding domains [6] with an N-terminal jelly roll-like fold and C-terminal modified b-trefoil fold containing a conserved ganglioside-binding site (SxWY) (Fig. 2).…”
Section: Structure Of the Bont/a5-binding Domain (H C /A5)supporting
confidence: 53%
“…Each BoNT serotype can be further categorised into subtypes based on amino acid sequence identity. For example, there are currently eight known subtypes of BoNT/A (/A1-/A8), which share between 84% and 97% sequence identity [6]. While BoNTs are the most toxic biological molecules known to science, they are used in human therapy, especially BoNT/A1 [7].…”
mentioning
confidence: 99%
“…One significant change involves a switch of buried α‐helical regions into a β‐hairpin structure that facilitates the embedding of the H N into the endosomal membrane . The LC domain is then translocated into the cytosol of neurons at the neuromuscular junction where it catalyses the cleavage of its target SNARE protein . Previously we had reported the crystal structure of H C /A3 at 1.6 Å resolution ; here, we report the structure of H C /A3 in complex with GD1a to 1.75 Å resolution and highlight the key structural changes that occur upon ganglioside binding.…”
mentioning
confidence: 78%
“…One significant change involves a switch of buried a-helical regions into a b-hairpin structure that facilitates the embedding of the H N into the endosomal membrane [12]. The LC domain is then translocated into the cytosol of neurons at the neuromuscular junction where it catalyses the cleavage of its target SNARE protein [13]. Previously we had reported the crystal structure of H C /A3 at 1.6…”
mentioning
confidence: 99%
“…The three domains are structurally separated in BoNT/A and B [ 26 , 27 ]. However, BoNT/E adopts a unique compact and ‘closed-wing’-like conformation, which may enable more facile interactions among the three domains and therefore lead to its fast onset of intoxication ( Figure 1 a) [ 28 , 29 ]. The BoNT intoxication mechanism involves three major steps [ 1 , 25 ].…”
Section: Introductionmentioning
confidence: 99%