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Molecules 2017, 22(7), 1101; doi:10.3390/molecules22071101

Sites for Dynamic Protein-Carbohydrate Interactions of O- and C-Linked Mannosides on the E. coli FimH Adhesin

Pharmaqam, Department of Chemistry, Université du Québec à Montréal, P. O. Box 8888, Succ. Centre-ville, Montréal, QC H3C 3P8, Canada
Department of Chemistry and Biochemistry, Université de Moncton, Moncton, NB E1A 3E9, Canada
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF), UMR8576 du CNRS, Université de Lille, F-59000 Lille, France
Center for Synthesis and Chemical Biology (CSCB), University College Dublin, Belfield, Dublin 4, Ireland
These authors contributed equally to this work.
Authors to whom correspondence should be addressed.
Received: 1 June 2017 / Revised: 25 June 2017 / Accepted: 28 June 2017 / Published: 3 July 2017
(This article belongs to the Special Issue Protein-Carbohydrate Interactions)
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Antagonists of the Escherichia coli type-1 fimbrial adhesin FimH are recognized as attractive alternatives for antibiotic therapies and prophylaxes against acute and recurrent bacterial infections. In this study α-d-mannopyranosides O- or C-linked with an alkyl, alkene, alkyne, thioalkyl, amide, or sulfonamide were investigated to fit a hydrophobic substituent with up to two aryl groups within the tyrosine gate emerging from the mannose-binding pocket of FimH. The results were summarized into a set of structure-activity relationships to be used in FimH-targeted inhibitor design: alkene linkers gave an improved affinity and inhibitory potential, because of their relative flexibility combined with a favourable interaction with isoleucine-52 located in the middle of the tyrosine gate. Of particular interest is a C-linked mannoside, alkene-linked to an ortho-substituted biphenyl that has an affinity similar to its O-mannosidic analog but superior to its para-substituted analog. Docking of its high-resolution NMR solution structure to the FimH adhesin indicated that its ultimate, ortho-placed phenyl ring is able to interact with isoleucine-13, located in the clamp loop that undergoes conformational changes under shear force exerted on the bacteria. Molecular dynamics simulations confirmed that a subpopulation of the C-mannoside conformers is able to interact in this secondary binding site of FimH. View Full-Text
Keywords: C-glycosidic linkage; ortho-biphenyl mannose; FimH; anti-adhesive; uropathogenic E. coli; clamp loop; dynamic binding C-glycosidic linkage; ortho-biphenyl mannose; FimH; anti-adhesive; uropathogenic E. coli; clamp loop; dynamic binding

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Touaibia, M.; Krammer, E.-M.; Shiao, T.C.; Yamakawa, N.; Wang, Q.; Glinschert, A.; Papadopoulos, A.; Mousavifar, L.; Maes, E.; Oscarson, S.; Vergoten, G.; Lensink, M.F.; Roy, R.; Bouckaert, J. Sites for Dynamic Protein-Carbohydrate Interactions of O- and C-Linked Mannosides on the E. coli FimH Adhesin. Molecules 2017, 22, 1101.

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