7ky2

Botulism Neurooxin Light Chain A app form

spinqualitylabelsall models 7ky2, resolution 2.78Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7ky2 is a 2 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 2.78Å Ligands: ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function BXA1_CLOBH 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Botulinum neurotoxin 3D structures

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