5MTS

Complex of FimH lectin with a TazMan (thiazolylaminomannosides) family member known as potent anti-adhesive agent at 2.6 A resolution

5MTS の概要

• エントリーDOI: 10.2210/pdb5mts/pdb
• 分子名称: Protein FimH, [2-[[(2~{S},3~{S},4~{S},5~{S},6~{R})-6-(hydroxymethyl)-3,4,5-tris(oxidanyl)oxan-2-yl]amino]-1,3-thiazol-5-yl]-(4-methyl-2-pyrazin-2-yl-1,3-thiazol-5-yl)methanone, NICKEL (II) ION, ... (4 entities in total)
• 機能のキーワード: cell adhesion, bacterial adhesin, type 1 fimbriae, urinary tract infection, crohn's disease
• 由来する生物種: Escherichia coli K-12
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 64024.91

構造登録者

de Ruyck, J.,Bouckaert, J. (登録日: 2017-01-10, 公開日: 2017-03-15, 最終更新日: 2024-10-23)

主引用文献

Alvarez Dorta, D.,Chalopin, T.,Sivignon, A.,de Ruyck, J.,Dumych, T.I.,Bilyy, R.O.,Deniaud, D.,Barnich, N.,Bouckaert, J.,Gouin, S.G.
Physiochemical Tuning of Potent Escherichia coli Anti-Adhesives by Microencapsulation and Methylene Homologation.
ChemMedChem, 12:986-998, 2017

PubMed Abstract: Thiazolylaminomannosides (TazMan) are FimH antagonists with anti-adhesive potential against adherent-invasive Escherichia coli (AIEC) promoting gut inflammation in patients with Crohn's disease. The lead TazMan is highly potent in vitro, but shows limited in vivo efficiency, probably due to low pH stability and water solubility. We recently developed a second generation of stable TazMan, but the anti-adhesive effect was lower than the first. Herein we report a co-crystal structure of the lead TazMan in FimH, revealing that the anomeric NH group and the second thiazole moiety provide a positive hydrogen bonding interaction with a trapped water molecule, and π-stacking with Tyr48 of FimH, respectively. Consequently, we developed NeoTazMan homologated with a methylene group for low-pH and mannosidase stability with a conserved NH group and bearing various heterocyclic aglycones. Microencapsulation of the lead NeoTazMan in γ-cyclodextrin dramatically improved water solubility without disrupting the affinity for FimH or the anti-adhesive effect against AIEC isolated from patients with Crohn's disease.

PubMed: 28257558
DOI: 10.1002/cmdc.201700061

実験手法

X-RAY DIFFRACTION (2.6 Å)