3QW5

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

3QW5 の概要

• エントリーDOI: 10.2210/pdb3qw5/pdb
• 関連するPDBエントリー: 3BWI 3C88 3C89 3C8A 3C8B 3DDA 3DDB 3QW6 3QW7 3QW8
• 分子名称: Botulinum neurotoxin type A, inhibitory peptide RRGF, ZINC ION, ... (5 entities in total)
• 機能のキーワード: endopeptidase, syntaxin, bio-warfare agent, membrane, metal-binding, metalloprotease, protease, secreted, transmembrane, snap25, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Clostridium botulinum
• 細胞内の位置: Botulinum neurotoxin A light chain: Secreted. Botulinum neurotoxin A heavy chain: Secreted: A5HZZ9
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 50303.96

構造登録者

Kumaran, D.,Swaminathan, S. (登録日: 2011-02-26, 公開日: 2012-02-08, 最終更新日: 2024-11-20)

主引用文献

Kumar, G.,Kumaran, D.,Ahmed, S.A.,Swaminathan, S.
Peptide inhibitors of botulinum neurotoxin serotype A: design, inhibition, cocrystal structures, structure-activity relationship and pharmacophore modeling.
Acta Crystallogr.,Sect.D, 68:511-520, 2012

PubMed Abstract: 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 µM 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.

PubMed: 22525749
DOI: 10.1107/S0907444912003551

実験手法

X-RAY DIFFRACTION (1.6 Å)