|Title||Study of the structural and dynamic effects in the FimH adhesin upon α-d-heptyl mannose binding.|
|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Vanwetswinkel, S., A. Volkov, Y. G. J. Sterckx, A. Garcia-Pino, L. Buts, W. F. Vranken, J. Bouckaert, R. Roy, L. Wyns, and N. A. J. van Nuland|
|Journal||J Med Chem|
|Date Published||2014 Feb 27|
|Keywords||Adhesins, Escherichia coli, Dimerization, Fimbriae Proteins, Mannose, Models, Molecular, Nuclear Magnetic Resonance, Biomolecular, Protein Binding, Protein Conformation|
Uropathogenic Escherichia coli cause urinary tract infections by adhering to mannosylated receptors on the human urothelium via the carbohydrate-binding domain of the FimH adhesin (FimHL). Numerous α-d-mannopyranosides, including α-d-heptyl mannose (HM), inhibit this process by interacting with FimHL. To establish the molecular basis of the high-affinity HM binding, we solved the solution structure of the apo form and the crystal structure of the FimHL-HM complex. NMR relaxation analysis revealed that protein dynamics were not affected by the sugar binding, yet HM addition promoted protein dimerization, which was further confirmed by small-angle X-ray scattering. Finally, to address the role of Y48, part of the "tyrosine gate" believed to govern the affinity and specificity of mannoside binding, we characterized the FimHL Y48A mutant, whose conformational, dynamical, and HM binding properties were found to be very similar to those of the wild-type protein.
|Alternate Journal||J. Med. Chem.|
Study of the structural and dynamic effects in the FimH adhesin upon α-d-heptyl mannose binding.