Sites for Dynamic Protein-Carbohydrate Interactions of O- and C-Linked Mannosides on the E. coli FimH Adhesin
AbstractAntagonists 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
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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.
Touaibia M, Krammer E-M, Shiao TC, Yamakawa N, Wang Q, Glinschert A, Papadopoulos A, Mousavifar L, Maes E, Oscarson S, Vergoten G, Lensink MF, 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(7):1101.Chicago/Turabian Style
Touaibia, Mohamed; Krammer, Eva-Maria; Shiao, Tze C.; Yamakawa, Nao; Wang, Qingan; Glinschert, Anja; Papadopoulos, Alex; Mousavifar, Leila; Maes, Emmanuel; Oscarson, Stefan; Vergoten, Gerard; Lensink, Marc F.; Roy, René; Bouckaert, Julie. 2017. "Sites for Dynamic Protein-Carbohydrate Interactions of O- and C-Linked Mannosides on the E. coli FimH Adhesin." Molecules 22, no. 7: 1101.
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