Lepsik, M, Sommer, R, Kuhaudomlarp, S et al. (5 more authors) (2019) Induction of rare conformation of oligosaccharide by binding to calcium-dependent bacterial lectin: X-ray crystallography and modelling study. European Journal of Medicinal Chemistry, 177. pp. 212-220. ISSN 0223-5234
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 Elsevier Masson SAS. All rights reserved. This is an author produced version of a paper published in European Journal of Medicinal Chemistry. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Lectin; Carbohydrate; Calcium ion; Quantum effect; Molecular dynamics; N-Acetyl |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 12 Jun 2019 14:57 |
Last Modified: | 18 May 2020 00:40 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.ejmech.2019.05.049 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:147214 |
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