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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

1
Pharmaqam, Department of Chemistry, Université du Québec à Montréal, P. O. Box 8888, Succ. Centre-ville, Montréal, QC H3C 3P8, Canada
2
Department of Chemistry and Biochemistry, Université de Moncton, Moncton, NB E1A 3E9, Canada
3
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF), UMR8576 du CNRS, Université de Lille, F-59000 Lille, France
4
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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Abstract

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
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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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