Study of the Structural and Dynamic Effects in the FimH Adhesin upon 伪-d-Heptyl Mannose Binding

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• 作者：Sophie Vanwetswinkel ; Alexander N. Volkov ; Yann G. J. Sterckx ; Abel Garcia-Pino ; Lieven Buts ; Wim F. Vranken ; Julie Bouckaert ; Ren茅 Roy ; Lode Wyns ; Nico A. J. van Nuland
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 27, 2014
• 年：2014
• 卷：57
• 期：4
• 页码：1416-1427
• 全文大小：633K
• 年卷期：v.57,no.4(February 27, 2014)
• ISSN：1520-4804

文摘

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 (FimH_L). Numerous 伪-d-mannopyranosides, including 伪-d-heptyl mannose (HM), inhibit this process by interacting with FimH_L. 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 FimH_L鈥揌M 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 鈥渢yrosine gate鈥?believed to govern the affinity and specificity of mannoside binding, we characterized the FimH_L Y48A mutant, whose conformational, dynamical, and HM binding properties were found to be very similar to those of the wild-type protein.