title: Structural Insight into Multivalent Galactoside Binding to Pseudomonas aeruginosa Lectin LecA.
abstract: Multivalent galactosides inhibiting Pseudomonas aeruginosa biofilms may help control this problematic pathogen. To understand the binding mode of tetravalent glycopeptide dendrimer GalAG2 [(Gal-β-OC6H4CO-Lys-Pro-Leu)4(Lys-Phe-Lys-Ile)2Lys-His-Ile-NH2] to its target lectin LecA, crystal structures of LecA complexes with divalent analog GalAG1 [(Gal-β-OC6H4CO-Lys-Pro-Leu)2Lys-Phe-Lys-Ile-NH2] and related glucose-triazole linked bis-galactosides 3u3 [Gal-β-O(CH2)n-(C2HN3)-4-Glc-β-(C2HN3)-[β-Glc-4-(N3HC2)]2-(CH2)n-O-β-Gal (n = 1)] and 5u3 (n = 3) were obtained, revealing a chelate bound 3u3, cross-linked 5u3, and monovalently bound GalAG1. Nevertheless, a chelate bound model better explaining their strong LecA binding and the absence of lectin aggregation was obtained by modeling for all three ligands. A model of the chelate bound GalAG2·LecA complex was also obtained rationalizing its unusually tight LecA binding (KD = 2.5 nM) and aggregation by lectin cross-linking. The very weak biofilm inhibition with divalent LecA inhibitors suggests that lectin aggregation is necessary for biofilm inhibition by GalAG2, pointing to multivalent glycoclusters as a unique opportunity to control P. aeruginosa biofilms.
authors: Department of Chemistry and Biochemistry, University of Berne , Freiestrasse 3, 3012 Berne, Switzerland.
authors: Ricardo
authors: R
authors: Visini
authors: Department of Chemistry and Biochemistry, University of Berne , Freiestrasse 3, 3012 Berne, Switzerland.
authors: Xian
authors: X
authors: Jin
authors: Department of Chemistry and Biochemistry, University of Berne , Freiestrasse 3, 3012 Berne, Switzerland.
authors: Myriam
authors: M
authors: Bergmann
authors: Department of Chemistry and Biochemistry, University of Berne , Freiestrasse 3, 3012 Berne, Switzerland.
authors: Gaelle
authors: G
authors: Michaud
authors: Department of Medicinal Chemistry & Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University , NL-3508 TB Utrecht, The Netherlands.
authors: Francesca
authors: F
authors: Pertici
authors: Department of Medicinal Chemistry & Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University , NL-3508 TB Utrecht, The Netherlands.
authors: Ou
authors: O
authors: Fu
authors: Department of Medicinal Chemistry & Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University , NL-3508 TB Utrecht, The Netherlands.
authors: Aliaksei
authors: A
authors: Pukin
authors: Department of Medicinal Chemistry & Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University , NL-3508 TB Utrecht, The Netherlands.
authors: Thomas R
authors: TR
authors: Branson
authors: Van't Hoff Laboratory for Physical and Colloid Chemistry, Debye Institute for Nanomaterials Science, Utrecht University , Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors: Dominique M E
authors: DM
authors: Thies-Weesie
authors: Department of Medicinal Chemistry & Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University , NL-3508 TB Utrecht, The Netherlands.
authors: Johan
authors: J
authors: Kemmink
authors: Centre de Recherches sur les Macromolécules Végétales, UPR5301, CNRS and Université Grenoble Alpes , 601 rue de la Chimie, F38041 Grenoble, France.
authors: Emilie
authors: E
authors: Gillon
authors: Centre de Recherches sur les Macromolécules Végétales, UPR5301, CNRS and Université Grenoble Alpes , 601 rue de la Chimie, F38041 Grenoble, France.
authors: Anne
authors: A
authors: Imberty
authors: Department of Chemistry and Biochemistry, University of Berne , Freiestrasse 3, 3012 Berne, Switzerland.
authors: Achim
authors: A
authors: Stocker
authors: Department of Chemistry and Biochemistry, University of Berne , Freiestrasse 3, 3012 Berne, Switzerland.
authors: Tamis
authors: T
authors: Darbre
authors: Department of Medicinal Chemistry & Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University , NL-3508 TB Utrecht, The Netherlands.
authors: Roland J
authors: RJ
authors: Pieters
authors: Department of Chemistry and Biochemistry, University of Berne , Freiestrasse 3, 3012 Berne, Switzerland.
authors: Jean-Louis
authors: JL
authors: Reymond
mesh_terms: D018829:Adhesins, Bacterial / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D002240:Carbohydrate Sequence; D056831:Coordination Complexes / Q000737:chemistry; D018360:Crystallography, X-Ray; D005697:Galactosides / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011550:Pseudomonas aeruginosa / Q000378:metabolism*
chemical_list: D018829:Adhesins, Bacterial; D056831:Coordination Complexes; D005697:Galactosides; C102929:LecA protein, bacteria