3ZL1

A thiazolyl-mannoside bound to FimH, monoclinic space group

Summary for 3ZL1

• Entry DOI: 10.2210/pdb3zl1/pdb
• Related: 3ZL2
• Descriptor: PROTEIN FIMH, N-{5-[(1R)-1-hydroxyethyl]-1,3-thiazol-2-yl}-alpha-D-mannopyranosylamine, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: cell adhesion, type-1 fimbriae, thiazole, crohn's disease, immunoglobulin
• Biological source: ESCHERICHIA COLI
• Cellular location: Fimbrium: P08191
• Total number of polymer chains: 2
• Total formula weight: 34477.75

Authors

Brument, S.,Sivignon, A.,Dumych, T.I.,Moreau, N.,Roos, G.,Guerardel, Y.,Chalopin, T.,Deniaud, D.,Bilyy, R.O.,Darfeuille-Michaud, A.,Bouckaert, J.,Gouin, S.G. (deposition date: 2013-01-27, release date: 2013-07-10, Last modification date: 2024-11-06)

Primary citation

Brument, S.,Sivignon, A.,Dumych, T.I.,Moreau, N.,Roos, G.,Guerardel, Y.,Chalopin, T.,Deniaud, D.,Bilyy, R.O.,Darfeuille-Michaud, A.,Bouckaert, J.,Gouin, S.G.
Thiazolylaminomannosides as Potent Antiadhesives of Type 1 Piliated Escherichia Coli Isolated from Crohn'S Disease Patients.
J.Med.Chem., 56:5395-, 2013

PubMed Abstract: Adherent-invasive Escherichia coli (AIEC) have previously been shown to induce gut inflammation in patients with Crohn's disease (CD). We developed a set of mannosides to prevent AIEC attachment to the gut by blocking the FimH bacterial adhesin. The crystal structure of the FimH lectin domain in complex with a lead thiazolylaminomannoside highlighted the preferential position for pharmacomodulations. A small library of analogues showing nanomolar affinity for FimH was then developed. Notably, AIEC attachment to intestinal cells was efficiently prevented by the most active compound and at around 10000-fold and 100-fold lower concentrations than mannose and the potent FimH inhibitor heptylmannoside, respectively. An ex vivo assay performed on the colonic tissue of a transgenic mouse model of CD confirmed this antiadhesive potential. Given the key role of AIEC in the chronic intestinal inflammation of CD patients, these results suggest a potential antiadhesive treatment with the FimH inhibitors developed.

PubMed: 23795713
DOI: 10.1021/JM400723N

Experimental method

X-RAY DIFFRACTION (1.551 Å)