Visini, Ricardo; Bergman, Manfred Max; Michaud, Gaelle; Pertici, Francesca; Fu, Ou; Pukin, Aliaksei; Branson, Thomas; Thies-Weesie, Dominique; Kemmink, Johan; Gillon, Emilie; Imberty, Anne; Stocker, Achim; Darbre, Tamis; Pieters, Roland; Reymond, Jean-Louis (2015). Structural Insight into Multivalent Galactoside Binding to Pseudomonas aeroginosa lectin LecA. ACS Chemical Biology, 10(11), pp. 2455-2462. American Chemical Society 10.1021/acschembio.5b00302
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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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP) |
UniBE Contributor: |
Visini, Ricardo, Bergman, Manfred Max (A), Stocker, Achim, Darbre, Tamis, Reymond, Jean-Louis |
Subjects: |
500 Science > 570 Life sciences; biology 500 Science > 540 Chemistry |
ISSN: |
1554-8929 |
Publisher: |
American Chemical Society |
Language: |
English |
Submitter: |
Achim Stocker |
Date Deposited: |
09 Nov 2015 10:58 |
Last Modified: |
29 Mar 2023 23:34 |
Publisher DOI: |
10.1021/acschembio.5b00302 |
BORIS DOI: |
10.7892/boris.72544 |
URI: |
https://boris.unibe.ch/id/eprint/72544 |
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