Abstract:
:Botulinum neurotoxin (BoNT) is a category A toxin that has been classified within seven serotypes, designated A-G. Recently, it has been discovered that sequence variability occurs in BoNTs produced by serotype A (BoNT/A) variant strains, designated as subtypes A1 and A2, which have significantly different antibody-binding properties. We have therefore made efforts to understand at the molecular level the diversity and its effects on the biological actions of the toxin, including receptor binding, substrate recognition, and catalysis. We provide the results of these studies, including the analysis of two newly sequenced BoNT/A variants, Loch Maree (A3) and 657Ba (A4), and their comparison to A1 and A2. Using sequence analysis, available functional data, molecular modeling, and comparison of models with the crystal structures of BoNT/A1 and the light chain of BoNT/A2, we conclude that these sequence differences within subtypes will impact development of broad-spectrum antibody and small ligand therapeutics, and suggest dissimilarities in binding affinity and cleavage efficiency of the SNAP-25 substrate. In particular, sequence variation in subtypes BoNT/A3 and BoNT/A4 will likely effect alpha-exosite and S1' subsite recognition, respectively.
journal_name
J Mol Bioljournal_title
Journal of molecular biologyauthors
Arndt JW,Jacobson MJ,Abola EE,Forsyth CM,Tepp WH,Marks JD,Johnson EA,Stevens RCdoi
10.1016/j.jmb.2006.07.040subject
Has Abstractpub_date
2006-09-29 00:00:00pages
733-42issue
4eissn
0022-2836issn
1089-8638pii
S0022-2836(06)00910-7journal_volume
362pub_type
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