3qw7 | pdb_00003qw7

Crystal structure of the protease domain of Botulinum Neurotoxin Serotype A with a peptide inhibitor RRFC

spinqualitylabelsall models 3qw7, resolution 1.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3qw7 is a 2 chain structure with sequence from Clostridium botulinum a str. hall. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: NA, SO4, ZN NonStd Res: NH2 Related: 3bwi, 3c88, 3c89, 3c8a, 3c8b, 3dda, 3ddb, 3qw5, 3qw6, 3qw8 Gene: botA, CBO0806, CLC_0862 (Clostridium botulinum A str. Hall) Activity: Bontoxilysin, with EC number 3.4.24.69 Resources: FirstGlance, OCA, RCSB, PDBsum 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 Clostridium botulinum neurotoxins are classified as Category A bioterrorism agents by the Centers for Disease Control and Prevention (CDC). The seven serotypes (A-G) of the botulinum neurotoxin, the causative agent of the disease botulism, block neurotransmitter release by specifically cleaving one of the three SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins and induce flaccid paralysis. Using a structure-based drug-design approach, a number of peptide inhibitors were designed and their inhibitory activity against botulinum serotype A (BoNT/A) protease was determined. The most potent peptide, RRGF, inhibited BoNT/A protease with an IC(50) of 0.9 microM and a K(i) of 358 nM. High-resolution crystal structures of various peptide inhibitors in complex with the BoNT/A protease domain were also determined. Based on the inhibitory activities and the atomic interactions deduced from the cocrystal structures, the structure-activity relationship was analyzed and a pharmacophore model was developed. Unlike the currently available models, this pharmacophore model is based on a number of enzyme-inhibitor peptide cocrystal structures and improved the existing models significantly, incorporating new features. Peptide inhibitors of botulinum neurotoxin serotype A: design, inhibition, cocrystal structures, structure-activity relationship and pharmacophore modeling.,Kumar G, Kumaran D, Ahmed SA, Swaminathan S Acta Crystallogr D Biol Crystallogr. 2012 May;68(Pt 5):511-20. Epub 2012 Apr 17. PMID:22525749 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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