3qw6
Crystal structure of the protease domain of Botulinum Neurotoxin Serotype A with a peptide inhibitor RYGCCrystal structure of the protease domain of Botulinum Neurotoxin Serotype A with a peptide inhibitor RYGC
Structural highlights
Publication Abstract from PubMedClostridium 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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