7kyh

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Botulism Neurooxin Light Chain A app form

Structural highlights

7kyh is a 4 chain structure with sequence from Clostridium botulinum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.91Å
Ligands:XBM, ZN
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

BXA1_CLOBO Inhibits acetylcholine release. The botulinum toxin binds with high affinity to peripheral neuronal presynaptic membrane to the secretory vesicle protein SV2. It binds directly to the largest luminal loop of SV2A, SV2B and SV2C. It is then internalized by receptor-mediated endocytosis. The C-terminus of the heavy chain (H) is responsible for the adherence of the toxin to the cell surface while the N-terminus mediates transport of the light chain from the endocytic vesicle to the cytosol. After translocation, the light chain (L) hydrolyzes the 197-Gln-|-Arg-198 bond in SNAP-25, thereby blocking neurotransmitter release. Inhibition of acetylcholine release results in flaccid paralysis, with frequent heart or respiratory failure.

Publication Abstract from PubMed

The botulinum neurotoxin, the caustic agent that causes botulism, is the most lethal toxin known to man. The neurotoxin composed of a heavy chain (HC) and a light chain (LC) enters neurons and cleaves SNARE proteins, leading to flaccid paralysis, which, in severe occurrences, can result in death. A therapeutic target for botulinum neurotoxin (BoNT) intoxication is the LC, a zinc metalloprotease that directly cleaves SNARE proteins. Herein we report dipeptides containing an aromatic connected to the N-terminus via a sulfonamide and a hydroxamic acid at the C-terminus as BoNT/A LC inhibitors. On the basis of a structure-activity relationship study, 33 was discovered to inhibit the BoNT/A LC with an IC50 of 21 nM. X-ray crystallography analysis of 30 and 33 revealed that the dipeptides inhibit through a competitive mechanism and identified several key intermolecular interactions.

Discovery of Dipeptides as Potent Botulinum Neurotoxin A Light-Chain Inhibitors.,Amezcua M, Cruz RS, Ku A, Moran W, Ortega ME, Salzameda NT ACS Med Chem Lett. 2021 Jan 27;12(2):295-301. doi:, 10.1021/acsmedchemlett.0c00674. eCollection 2021 Feb 11. PMID:33603978[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
1 reviews cite this structure
Toxicology and pharmacology of botulinum and tetanus neurotoxins: an update.
Pirazzini et al. (2022)
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0 other articles
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See Also

References

  1. ↑ Amezcua M, Cruz RS, Ku A, Moran W, Ortega ME, Salzameda NT. Discovery of Dipeptides as Potent Botulinum Neurotoxin A Light-Chain Inhibitors. ACS Med Chem Lett. 2021 Jan 27;12(2):295-301. PMID:33603978 doi:10.1021/acsmedchemlett.0c00674

Contents


PDB ID 7kyh

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OCA

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