1uwf

From Proteopedia

Revision as of 10:49, 5 November 2007

1.7 A RESOLUTION STRUCTURE OF THE RECEPTOR BINDING DOMAIN OF THE FIMH ADHESIN FROM UROPATHOGENIC E. COLI

Overview

Mannose-binding type 1 pili are important virulence factors for the, establishment of Escherichia coli urinary tract infections (UTIs). These, infections are initiated by adhesion of uropathogenic E. coli to uroplakin, receptors in the uroepithelium via the FimH adhesin located at the tips of, type 1 pili. Blocking of bacterial adhesion is able to prevent infection., Here, we provide for the first time binding data of the molecular events, underlying type 1 fimbrial adherence, by crystallographic analyses of the, FimH receptor binding domains from a uropathogenic and a K-12 strain, and, affinity measurements with mannose, common mono- and disaccharides, and a, series of alkyl and aryl mannosides. Our results illustrate that the, lectin domain of the FimH adhesin is a stable and functional entity and, that an exogenous butyl alpha-D-mannoside, bound in the crystal, structures, exhibits a significantly better affinity for FimH (Kd = 0.15, microM) than mannose (Kd = 2.3 microM). Exploration of the binding, affinities of alpha- d-mannosides with longer alkyl tails revealed, affinities up to 5 nM. Aryl mannosides and fructose can also bind with, high affinities to the FimH lectin domain, with a 100-fold improvement and, 15-fold reduction in affinity, respectively, compared with mannose. Taken, together, these relative FimH affinities correlate exceptionally well with, the relative concentrations of the same glycans needed for the inhibition, of adherence of type 1 piliated E. coli. We foresee that our findings will, spark new ideas and initiatives for the development of UTI vaccines and, anti-adhesive drugs to prevent anticipated and recurrent UTIs.

About this Structure

1UWF is a Single protein structure of sequence from Escherichia coli with DEG and GOL as ligands. Structure known Active Site: AC1. Full crystallographic information is available from OCA.

Reference

Receptor binding studies disclose a novel class of high-affinity inhibitors of the Escherichia coli FimH adhesin., Bouckaert J, Berglund J, Schembri M, De Genst E, Cools L, Wuhrer M, Hung CS, Pinkner J, Slattegard R, Zavialov A, Choudhury D, Langermann S, Hultgren SJ, Wyns L, Klemm P, Oscarson S, Knight SD, De Greve H, Mol Microbiol. 2005 Jan;55(2):441-55. PMID:15659162

Page seeded by OCA on Mon Nov 5 12:54:38 2007