Structural basis for oligosaccharide-mediated adhesion of P. aeruginosa in the lungs of cystic fibrosis patients

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Authors

MITCHELL Edward HOULES Corrine SABIN Charles WIMMEROVÁ Michaela GAUTIER Catherine PEREZ Serge WU Albert M. GILBOA-GARBER Nechama IMBERTY Anne

Year of publication 2003
Type Article in Proceedings
Conference 12th European Carbohydrate Symposium
MU Faculty or unit

Faculty of Science

Citation
Field Biochemistry
Keywords Pseudomonas aeruginosa; lectin; microcalorimetry; crystal structure; cystic fibrosis
Description The galactose- and fucose-binding (PA-IL and PA-IIL) lectins of Pseudomonas aeruginosa contribute to the virulence of this pathogenic bacterium, which is a major cause of morbidity and mortality in cystic fibrosis (CF) patients via chronic lung colonisation. CF gene mutations increase cell surface fucosylation and CF patients also display modifications in their respiratory and salivary mucins with a higher percentage of sialylated and sulphated oligosaccharides. These cystic fibrosis mucins and cell surface glycoconjugates carry fucose as the terminal sugar residue. Since the P. aeruginosa lectins have been characterised to reveal an outstandingly high affinity of PA-IIL for fucose, they can serve as binding targets for binding by PA-IIL [1]. Precise three-dimensional knowledge of the lectin sugar binding site, through protein crystallography at high resolution, has allowed the unusually high affinity to be understood and shown a novel sugar binding mode. Subsequent modelling studies, based on the fucose complex structure, and binding studies have demonstrated that the preferred ligands of this bacterial lectin belong to the Lea series. Such structure-based knowledge could be used for the design of efficient anti-bacterial compounds and, furthermore, the unusually high affinity interaction of this novel binding mode suggests that PA-IIL may be a useful target for oligosaccharide-based therapeutics.
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