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Induction of rare conformation of oligosaccharide by binding to calcium-dependent bacterial lectin: X-ray crystallography and modelling study.
Lepsik, Martin Sommer, Roman Kuhaudomlarp, Sakonwan Lelimousin, Mickaël Paci, Emanuele Varrot, Annabelle Imberty, Anne
Lepsik, Martin
Sommer, Roman
Kuhaudomlarp, Sakonwan
Lelimousin, Mickaël
Paci, Emanuele
Varrot, Annabelle
Imberty, Anne
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2019-09-01
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Abstract
Pathogenic micro-organisms utilize protein receptors (lectins) in adhesion to host tissues, a process that in some cases relies on the interaction between lectins and human glycoconjugates. Oligosaccharide epitopes are recognized through their three-dimensional structure and their flexibility is a key issue in specificity. In this paper, we analysed by X-ray crystallography the structures of the LecB lectin from two strains of Pseudomonas aeruginosa in complex with Lewis x oligosaccharide present on cell surfaces of human tissues. An unusual conformation of the glycan was observed in all binding sites with a non-canonical syn orientation of the N-acetyl group of N-acetyl-glucosamine. A PDB-wide search revealed that such an orientation occurs only in 4% of protein/carbohydrate complexes. Theoretical chemistry calculations showed that the observed conformation is unstable in solution but stabilised by the lectin. A reliable description of LecB/Lewis x complex by force field-based methods had proven especially challenging due to the special feature of the binding site, two closely apposed Ca2+ ions which induce strong charge delocalisation. By comparing various force-field parametrisations, we propose a general strategy which will be useful in near future for designing carbohydrate-based ligands (glycodrugs) against other calcium-dependent protein receptors.
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Eur J Med Chem. 2019 Sep 1;177:212-220. doi: 10.1016/j.ejmech.2019.05.049. Epub 2019 May 18.
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en
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1768-3254