title: Structural basis for the interaction between human milk oligosaccharides and the bacterial lectin PA-IIL of Pseudomonas aeruginosa.
abstract: One of the mechanisms contributing to the protection by breast-feeding of the newborn against enteric diseases is related to the ability of human milk oligosaccharides to prevent the attachment of pathogenic bacteria to the duodenual epithelium. Indeed, a variety of fucosylated oligosaccharides, specific to human milk, form part of the innate immune system. In the present study, we demonstrate the specific blocking of PA-IIL, a fucose-binding lectin of the human pathogen Pseudomonas aeruginosa, by milk oligosaccharides. Two fucosylated epitopes, Lewis a and 3-fucosyl-lactose (Lewis x glucose analogue) bind to the lectin with dissociation constants of 2.2x10(-7) M and 3.6x10(-7) M respectively. Thermodynamic studies indicate that these interactions are dominated by enthalpy. The entropy contribution is slightly favourable when binding to fucose and to the highest-affinity ligand, Lewis a. The high-resolution X-ray structures of two complexes of PA-IIL with milk oligosaccharides allow the precise determination of the conformation of a trisaccharide and a pentasaccharide. The different types of interaction between the oligosaccharides and the protein involve not only hydrogen bonding, but also calcium- and water-bridged contacts, allowing a rationalization of the thermodynamic data. This study provides important structural information about compounds that could be of general application in new therapeutic strategies against bacterial infections.
authors.affiliation: Centre de Recherches sur les Macromolécules Végétales, CNRS, Université Joseph Fourier, BP53, 38041 Grenoble Cedex 09, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Perret
authors.forename: Charles
authors.initials: C
authors.lastname: Sabin
authors.forename: Claire
authors.initials: C
authors.lastname: Dumon
authors.forename: Martina
authors.initials: M
authors.lastname: Pokorná
authors.forename: Catherine
authors.initials: C
authors.lastname: Gautier
authors.forename: Oxana
authors.initials: O
authors.lastname: Galanina
authors.forename: Shahov
authors.initials: S
authors.lastname: Ilia
authors.forename: Nicolai
authors.initials: N
authors.lastname: Bovin
authors.forename: Magali
authors.initials: M
authors.lastname: Nicaise
authors.forename: Michel
authors.initials: M
authors.lastname: Desmadril
authors.forename: Nechama
authors.initials: N
authors.lastname: Gilboa-Garber
authors.forename: Michaela
authors.initials: M
authors.lastname: Wimmerová
authors.forename: Edward P
authors.initials: EP
authors.lastname: Mitchell
authors.forename: Anne
authors.initials: A
authors.lastname: Imberty
mesh_terms: D018829:Adhesins, Bacterial / Q000378:metabolism*; D001665:Binding Sites; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D003461:Crystallography; D006801:Humans; D037102:Lectins / Q000378:metabolism*; D008895:Milk, Human / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009844:Oligosaccharides / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D011550:Pseudomonas aeruginosa / Q000737:chemistry* / Q000378:metabolism; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D018829:Adhesins, Bacterial; D037102:Lectins; D009844:Oligosaccharides; C038692:adhesin, Pseudomonas