4HEV

Clostridium Botulinum Serotype A Light Chain Inhibited By Adamantane Hydroxamate

4HEV の概要

• エントリーDOI: 10.2210/pdb4hev/pdb
• 分子名称: Botulinum neurotoxin type A light chain, ZINC ION, N-hydroxy-2-[(3S,5S,7S)-tricyclo[3.3.1.1~3,7~]dec-1-yl]acetamide, ... (4 entities in total)
• 機能のキーワード: zn2+-dependent metalloprotease, 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: P10845
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 101753.48

構造登録者

Silvaggi, N.R.,Allen, K.N. (登録日: 2012-10-04, 公開日: 2013-01-23, 最終更新日: 2023-09-20)

主引用文献

Silhar, P.,Silvaggi, N.R.,Pellett, S.,Johnson, E.A.,Allen, K.N.,Janda, K.D.
Evaluation of adamantane hydroxamates as botulinum neurotoxin inhibitors: synthesis, crystallography, modeling, kinetic and cellular based studies.
Bioorg.Med.Chem., 21:1344-1348, 2013

PubMed Abstract: Botulinum neurotoxins (BoNTs) are the most lethal biotoxins known to mankind and are responsible for the neuroparalytic disease botulism. Current treatments for botulinum poisoning are all protein based and thus have a limited window of treatment opportunity. Inhibition of the BoNT light chain protease (LC) has emerged as a therapeutic strategy for the treatment of botulism as it may provide an effective post exposure remedy. Using a combination of crystallographic and modeling studies a series of hydroxamates derived from 1-adamantylacetohydroxamic acid (3a) were prepared. From this group of compounds, an improved potency of about 17-fold was observed for two derivatives. Detailed mechanistic studies on these structures revealed a competitive inhibition model, with a K(i)=27 nM, which makes these compounds some of the most potent small molecule, non-peptidic BoNT/A LC inhibitors reported to date.

PubMed: 23340139
DOI: 10.1016/j.bmc.2012.12.001

実験手法

X-RAY DIFFRACTION (2.5 Å)