5V8U

Small Molecule Inhibitor ABS-143 Bound to the Botulinum Neurotoxin Serotype A Light Chain

5V8U の概要

• エントリーDOI: 10.2210/pdb5v8u/pdb
• 関連するPDBエントリー: 5V8P 5V8R
• 分子名称: Botulinum neurotoxin type A, ZINC ION, N-[3-(4-fluorophenyl)-4-methyl-1H-pyrazol-5-yl]-2-sulfanylacetamide, ... (4 entities in total)
• 機能のキーワード: metalloprotease, drug design, 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: 102295.98

構造登録者

Allen, K.N.,Silvaggi, N.R. (登録日: 2017-03-22, 公開日: 2017-07-26, 最終更新日: 2023-10-04)

主引用文献

Jacobson, A.R.,Adler, M.,Silvaggi, N.R.,Allen, K.N.,Smith, G.M.,Fredenburg, R.A.,Stein, R.L.,Park, J.B.,Feng, X.,Shoemaker, C.B.,Deshpande, S.S.,Goodnough, M.C.,Malizio, C.J.,Johnson, E.A.,Pellett, S.,Tepp, W.H.,Tzipori, S.
Small molecule metalloprotease inhibitor with in vitro, ex vivo and in vivo efficacy against botulinum neurotoxin serotype A.
Toxicon, 137:36-47, 2017

PubMed Abstract: Botulinum neurotoxins (BoNTs) are the most toxic substances known to mankind and are the causative agents of the neuroparalytic disease botulism. Their ease of production and extreme toxicity have caused these neurotoxins to be classified as Tier 1 bioterrorist threat agents and have led to a sustained effort to develop countermeasures to treat intoxication in case of a bioterrorist attack. While timely administration of an approved antitoxin is effective in reducing the severity of botulism, reversing intoxication requires different strategies. In the present study, we evaluated ABS 252 and other mercaptoacetamide small molecule active-site inhibitors of BoNT/A light chain using an integrated multi-assay approach. ABS 252 showed inhibitory activity in enzymatic, cell-based and muscle activity assays, and importantly, produced a marked delay in time-to-death in mice. The results suggest that a multi-assay approach is an effective strategy for discovery of potential BoNT therapeutic candidates.

PubMed: 28698055
DOI: 10.1016/j.toxicon.2017.06.016

実験手法

X-RAY DIFFRACTION (2.05 Å)