Structural Insight into Multivalent Galactoside Binding to Pseudomonas aeruginosa Lectin LecA

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• 作者：Ricardo Visini ; Xian Jin ; Myriam Bergmann ; Gaelle Michaud ; Francesca Pertici ; Ou Fu ; Aliaksei Pukin ; Thomas R. Branson ; Dominique M. E. Thies-Weesie ; Johan Kemmink ; Emilie Gillon ; Anne Imberty ; Achim Stocker ; Tamis Darbre ; Roland J. Pieters ; Jean-Louis Reymond
• 刊名：ACS Chemical Biology
• 出版年：2015
• 出版时间：November 20, 2015
• 年：2015
• 卷：10
• 期：11
• 页码：2455-2462
• 全文大小：638K
• ISSN：1554-8937

文摘

Multivalent galactosides inhibiting Pseudomonas aeruginosa biofilms may help control this problematic pathogen. To understand the binding mode of tetravalent glycopeptide dendrimer GalAG2 [(Gal-尾-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-尾-OC₆H₄CO-Lys-Pro-Leu)₂Lys-Phe-Lys-Ile-NH₂] and related glucose-triazole linked bis-galactosides 3u3 [Gal-尾-O(CH₂)_n-(C₂HN₃)-4-Glc-尾-(C₂HN₃)-[尾-Glc-4-(N₃HC₂)]₂-(CH₂)_n-O-尾-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路LecA complex was also obtained rationalizing its unusually tight LecA binding (K_D = 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.