5BQU

Crystal structure of HA17-HA33-Lactulose

5BQU の概要

• エントリーDOI: 10.2210/pdb5bqu/pdb
• 関連するPDBエントリー: 4LO1
• 関連するBIRD辞書のPRD_ID: PRD_900038
• 分子名称: HA-33, HA-17, beta-D-galactopyranose-(1-4)-beta-D-fructofuranose, ... (4 entities in total)
• 機能のキーワード: botulinum neurotoxin a, hemagglutinin, iptg, protein binding
• 由来する生物種: Clostridium botulinum; 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 85917.10

構造登録者

Lee, K.,Lam, K.,Jin, R. (登録日: 2015-05-29, 公開日: 2015-10-14, 最終更新日: 2024-03-06)

主引用文献

Lee, K.,Lam, K.H.,Kruel, A.M.,Mahrhold, S.,Perry, K.,Cheng, L.W.,Rummel, A.,Jin, R.
Inhibiting oral intoxication of botulinum neurotoxin A complex by carbohydrate receptor mimics.
Toxicon, 107:43-49, 2015

PubMed Abstract: Botulinum neurotoxins (BoNTs) cause the disease botulism manifested by flaccid paralysis that could be fatal to humans and animals. Oral ingestion of the toxin with contaminated food is one of the most common routes for botulism. BoNT assembles with several auxiliary proteins to survive in the gastrointestinal tract and is subsequently transported through the intestinal epithelium into the general circulation. Several hemagglutinin proteins form a multi-protein complex (HA complex) that recognizes host glycans on the intestinal epithelial cell surface to facilitate BoNT absorption. Blocking carbohydrate binding to the HA complex could significantly inhibit the oral toxicity of BoNT. Here, we identify lactulose, a galactose-containing non-digestible sugar commonly used to treat constipation, as a prototype inhibitor against oral BoNT/A intoxication. As revealed by a crystal structure, lactulose binds to the HA complex at the same site where the host galactose-containing carbohydrate receptors bind. In vitro assays using intestinal Caco-2 cells demonstrated that lactulose inhibits HA from compromising the integrity of the epithelial cell monolayers and blocks the internalization of HA. Furthermore, co-administration of lactulose significantly protected mice against BoNT/A oral intoxication in vivo. Taken together, these data encourage the development of carbohydrate receptor mimics as a therapeutic intervention to prevent BoNT oral intoxication.

PubMed: 26272706
DOI: 10.1016/j.toxicon.2015.08.003

実験手法

X-RAY DIFFRACTION (2.38 Å)