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Structural Insight into Multivalent Galactoside Binding to Pseudomonas aeruginosa Lectin LecA

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Visini Ricardo, Jin Xian, Bergmann Myriam, Michaud Gaëlle, 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,
Project A Chemical Space Approach to Bioactive Peptides
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Original article (peer-reviewed)

Journal ACS Chemical Biology
Volume (Issue) 10
Page(s) 2455 - 2462
Title of proceedings ACS Chemical Biology
DOI 10.1021/acschembio.5b00302

Open Access

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.
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