Journal ArticleDOI
Crystal structure of botulinum neurotoxin type A and implications for toxicity.
TLDR
The crystal structure of the entire 1,285 amino acid di-chain neurotoxin was determined and the toxin appears as a hybrid of varied structural motifs and suggests a modular assembly of functional subunits to yield pathogenesis.Abstract:
Botulinum neurotoxin type A (BoNT/A) is the potent disease agent in botulism, a potential biological weapon and an effective therapeutic drug for involuntary muscle disorders. The crystal structure of the entire 1,285 amino acid di-chain neurotoxin was determined at 3.3 A resolution. The structure reveals that the translocation domain contains a central pair of alpha-helices 105 A long and a approximately 50 residue loop or belt that wraps around the catalytic domain. This belt partially occludes a large channel leading to a buried, negative active site--a feature that calls for radically different inhibitor design strategies from those currently used. The fold of the translocation domain suggests a mechanism of pore formation different from other toxins. Lastly, the toxin appears as a hybrid of varied structural motifs and suggests a modular assembly of functional subunits to yield pathogenesis.read more
Citations
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Journal ArticleDOI
Characterisation of botulinum toxins type A and B, by matrix-assisted laser desorption ionisation and electrospray mass spectrometry
TL;DR: It was found that matrix-assisted laser desorption ionisation MS provides provisional identification from trypsin digest peptide maps and that liquid chromatography electrospray (tandem) mass spectrometry affords unequivocal identification from amino acid sequence information of digest peptides obtained intrypsin or pepsin digestion.
Journal ArticleDOI
Small molecule inhibitors as countermeasures for botulinum neurotoxin intoxication
TL;DR: There is an urgent need to identify and develop inhibitors that will serve as both prophylactic agents and post-exposure ‘rescue’ therapeutics for BoNT intoxication.
Journal ArticleDOI
Exchange of the HCC domain mediating double receptor recognition improves the pharmacodynamic properties of botulinum neurotoxin
TL;DR: It is demonstrated that the HCC serotype can modulate the affinity of the HC fragment for neuronal membranes as well as the potency of full‐length BoNT by replacing the BoNT/A HCC domain with the Bo NT/B HCC, BoNT /C HCC andBoNT/E HCC domains, which exhibit higher affinity for synaptosomes.
Journal ArticleDOI
Active-site mutagenesis of tetanus neurotoxin implicates TYR-375 and GLU-271 in metalloproteolytic activity
Ornella Rossetto,Paola Caccin,Michela Rigoni,Fiorella Tonello,Nicola Bortoletto,Raymond C. Stevens,Cesare Montecucco +6 more
TL;DR: Results demonstrate that both Glu-271 and Tyr-375 are essential for the proteolytic activity of TeNT.
Journal ArticleDOI
Hsp90 is involved in the entry of clostridial neurotoxins into the cytosol of nerve terminals
Domenico Azarnia Tehran,Marco Pirazzini,Oneda Leka,Andrea Mattarei,Florigio Lista,Thomas Binz,Ornella Rossetto,Cesare Montecucco +7 more
TL;DR: It is reported that geldanamycin, a specific inhibitor of heat shock protein 90, hampers the refolding of L after membrane translocation and completely prevents the cleavage of SNAREs, suggesting that the processes of L chain refolding and interchain disulfide reduction are strictly coupled.
References
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