Structural Insight into Multivalent Galactoside Binding to Pseudomonas aeroginosa lectin LecA

Visini, Ricardo; Bergmann, Myriam; 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 > Departement of Chemistry and Biochemistry

UniBE Contributor:

Visini, Ricardo; Bergmann, Myriam; Stocker, Achim; Darbre, Tamis and 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:

26 Jun 2016 02:08

Publisher DOI:

10.1021/acschembio.5b00302

BORIS DOI:

10.7892/boris.72544

URI:

https://boris.unibe.ch/id/eprint/72544

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