title: Carbohydrate-Lectin Interactions: An Unexpected Contribution to Affinity.
abstract: Uropathogenic E. coli exploit PapG-II adhesin for infecting host cells of the kidney; the expression of PapG-II at the tip of bacterial pili correlates with the onset of pyelonephritis in humans, a potentially life-threatening condition. It was envisaged that blocking PapG-II (and thus bacterial adhesion) would provide a viable therapeutic alternative to conventional antibiotic treatment. In our search for potent PapG-II antagonists, we observed an increase in affinity when tetrasaccharide 1, the natural ligand of PapG-II in human kidneys, was elongated to hexasaccharide 2, even though the additional Siaα(2-3)Gal extension is not in direct contact with the lectin. ITC studies suggest that the increased affinity results from partial desolvation of nonbinding regions of the hexasaccharide; this is ultimately responsible for perturbation of the outer hydration layers. Our results are in agreement with previous observations and suggest a general mechanism for modulating carbohydrate-protein interactions based on nonbinding regions of the ligand.
authors.affiliation: Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.
authors.forename: Giulio
authors.initials: G
authors.lastname: Navarra
authors.affiliation: Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Zihlmann
authors.affiliation: Biozentrum, Focal Area Structural Biology, University of Basel, Klingelbergstrasse 70, 4056, Basel, Switzerland.
authors.forename: Roman P
authors.initials: RP
authors.lastname: Jakob
authors.affiliation: Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.
authors.forename: Katja
authors.initials: K
authors.lastname: Stangier
authors.affiliation: Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.
authors.forename: Roland C
authors.initials: RC
authors.lastname: Preston
authors.affiliation: Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.
authors.forename: Said
authors.initials: S
authors.lastname: Rabbani
authors.affiliation: Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Smiesko
authors.affiliation: Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.
authors.forename: Bea
authors.initials: B
authors.lastname: Wagner
authors.affiliation: Biozentrum, Focal Area Structural Biology, University of Basel, Klingelbergstrasse 70, 4056, Basel, Switzerland.
authors.forename: Timm
authors.initials: T
authors.lastname: Maier
authors.affiliation: Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Ernst
mesh_terms: D018829:Adhesins, Bacterial / Q000737:chemistry / Q000378:metabolism*; D018830:Adhesins, Escherichia coli / Q000737:chemistry*; D001665:Binding Sites; D050260:Carbohydrate Metabolism; D002241:Carbohydrates / Q000737:chemistry; D018360:Crystallography, X-Ray; D036781:Fimbriae Proteins / Q000737:chemistry*; D006801:Humans; D037102:Lectins / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D011704:Pyelonephritis / Q000382:microbiology / Q000503:physiopathology
chemical_list: D018829:Adhesins, Bacterial; D018830:Adhesins, Escherichia coli; D002241:Carbohydrates; D037102:Lectins; C092426:PapG protein, E coli; D036781:Fimbriae Proteins
keywords: PapG; X-ray diffraction; antiadhesive; pyelonephritis; thermodynamics