ArticleThe Journal of biological chemistry2012
Structural framework for covalent inhibition of Clostridium botulinum neurotoxin A by targeting Cys165.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 25 citations in OpenAlex.
- Identification and characterization of botulinum neurotoxin-like two-component toxins inScience advances · 2025Article
- Bifunctional Inhibition of Botulinum Neurotoxin A Protease: Unexpected Active Site Inhibition Enhances Covalent Targeting of an Allosteric Site.Journal of medicinal chemistry · 2025Article
- Emerging opportunities for intact and native protein analysis using chemical proteomics.Analytica chimica acta · 2025Review
- Transformation of a Metal Chelate into a "Catch and Anchor" Inhibitor of Botulinum A Protease.International journal of molecular sciences · 2023Article
- Irreversible inhibition of BoNT/A protease: proximity-driven reactivity contingent upon a bifunctional approach.RSC medicinal chemistry · 2021Article
- Catch and Anchor Approach To Combat Both Toxicity and Longevity of Botulinum Toxin A.Journal of medicinal chemistry · 2020Article
- Covalent Modifiers of Botulinum Neurotoxin Counteract Toxin Persistence.ACS chemical biology · 2019Article
- A novel role of C-terminus in introducing a functionally flexible structure critical for the biological activity of botulinum neurotoxin.Scientific reports · 2018Article
- Metal Ions Effectively Ablate the Action of Botulinum Neurotoxin A.Journal of the American Chemical Society · 2017Article
- Cellular Protection of SNAP-25 against Botulinum Neurotoxin/A: Inhibition of Thioredoxin Reductase through a Suicide Substrate Mechanism.Journal of the American Chemical Society · 2016Article
- Article
- Benzoquinones as inhibitors of botulinum neurotoxin serotype A.Bioorganic & medicinal chemistry · 2014Article
- Targeting botulinum A cellular toxicity: a prodrug approach.Journal of medicinal chemistry · 2013Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Clostridium botulinum neurotoxin type A (BoNT/A) is one of the most potent toxins for humans and a major biothreat agent. Despite intense chemical efforts over the past 10 years to develop inhibitors of its catalytic domain (catBoNT/A), highly potent and selective inhibitors are still lacking. Recently, small inhibitors were reported to covalently modify catBoNT/A by targeting Cys(165), a residue located in the enzyme active site just above the catalytic zinc ion. However, no direct proof of Cys(165) modification was reported, and the poor accessibility of this residue in the x-ray structure of catBoNT/A raises concerns about this proposal. To clarify this issue, the functional role of Cys(165) was first assessed through a combination of site-directed mutagenesis and structural studies. These data suggested that Cys(165) is more involved in enzyme catalysis rather than in structural property. Then by peptide mass fingerprinting and x-ray crystallography, we demonstrated that a small compound containing a sulfonyl group acts as inhibitor of catBoNT/A through covalent modification of Cys(165). The crystal structure of this covalent complex offers a structural framework for developing more potent covalent inhibitors catBoNT/A. Other zinc metalloproteases can be founded in the protein database with a cysteine at a similar location, some expressed by major human pathogens; thus this work should find broader applications for developing covalent inhibitors.
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