1. Structural Insight into Multivalent Galactoside Binding to Pseudomonas aeruginosa Lectin LecA
- Author
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Visini, Ricardo, Jin, Xian, Bergmann, Myriam, Michaud, Gaelle, Pertici, Francesca, Fu, Ou, Pukin, Aliaksei, Branson, Thomas R., Thies-Weesie, Dominique M E, Kemmink, Johan, Gillon, Emilie, Imberty, Anne, Stocker, Achim, Darbre, Tamis, Pieters, Roland J., Reymond, Jean Louis, Physical and Colloid Chemistry, Sub Medicinal Chemistry & Chemical biol., LS Infectiebiologie (Bacteriologie), Sub Physical and Colloid Chemistry, UIPS - Utrecht Institute for Pharmaceutical Sciences, Physical and Colloid Chemistry, Sub Medicinal Chemistry & Chemical biol., LS Infectiebiologie (Bacteriologie), Sub Physical and Colloid Chemistry, and UIPS - Utrecht Institute for Pharmaceutical Sciences
- Subjects
Models, Molecular ,Stereochemistry ,Molecular Sequence Data ,Molecular Dynamics Simulation ,Crystallography, X-Ray ,medicine.disease_cause ,Biochemistry ,Divalent ,Galactosides ,Coordination Complexes ,Dendrimer ,medicine ,Binding site ,Adhesins, Bacterial ,chemistry.chemical_classification ,Binding Sites ,biology ,Pseudomonas aeruginosa ,Biofilm ,Lectin ,General Medicine ,Carbohydrate Sequence ,chemistry ,Galactoside binding ,biology.protein ,Molecular Medicine - 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.
- Published
- 2015