4AVK

Structure of trigonal FimH lectin domain crystal soaked with an alpha- D-mannoside O-linked to propynyl pyridine at 2.4A resolution

4AVK の概要

• エントリーDOI: 10.2210/pdb4avk/pdb
• 関連するPDBエントリー: 4ATT 4AUJ 4AUU 4AUY 4AV0 4AV4 4AV5 4AVH 4AVI 4AVJ
• 分子名称: FIMH, 3-(pyridin-3-yl)prop-2-yn-1-yl alpha-D-mannopyranoside, NICKEL (II) ION, ... (5 entities in total)
• 機能のキーワード: cell adhesion, bacterial adhesin, type 1 fimbriae, urinary tract infection, variable immunoglobulin fold
• 由来する生物種: ESCHERICHIA COLI
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 34925.87

構造登録者

Wellens, A.,Lahmann, M.,Touaibia, M.,Vaucher, J.,Oscarson, S.,Roy, R.,Remaut, H.,Bouckaert, J. (登録日: 2012-05-26, 公開日: 2012-06-27, 最終更新日: 2024-10-16)

主引用文献

Wellens, A.,Lahmann, M.,Touaibia, M.,Vaucher, J.,Oscarson, S.,Roy, R.,Remaut, H.,Bouckaert, J.
The Tyrosine Gate as a Potential Entropic Lever in the Receptor-Binding Site of the Bacterial Adhesin Fimh.
Biochemistry, 51:4790-, 2012

PubMed Abstract: Uropathogenic Escherichia coli (UPEC) are the major causative agents of urinary tract infections. During infection, UPEC adhere to mannosylated glycoreceptors on the urothelium via the FimH adhesin located at the tip of type 1 pili. Synthetic FimH antiadhesives such as alkyl and phenyl α-D-mannopyranosides are thus ideal candidates for the chemical interception of this crucial step in pathogenesis. The crystal structures of the FimH lectin domain in its ligand-free form and in complexes with eight medium- and high-affinity mannopyranoside inhibitors are presented. The thermodynamic profiles of the FimH-inhibitor interactions indicate that the binding of FimH to α-D-mannopyranose is enthalpy-driven and has a negative entropic change. Addition of a hydrophobic aglycon influences the binding enthalpy and can induce a favorable entropic change. The alleviation of the entropic cost is at least in part explained by increased dynamics in the tyrosine gate (Tyr48 and Tyr137) of the FimH receptor-binding site upon binding of the ligand. Ligands with a phenyl group directly linked to the anomeric oxygen of α-D-mannose introduce the largest dynamics into the Tyr48 side chain, because conjugation with the anomeric oxygen of α-D-mannose forces the aromatic aglycon into a conformation that comes into close contact (≈2.65 Å) with Tyr48. A propargyl group in this position predetermines the orientation of the aglycon and significantly decreases affinity. FimH has the highest affinity for α-D-mannopyranosides substituted with hydrophobic aglycons that are compatible in shape and electrostatic properties to the tyrosine gate, such as heptyl α-D-mannose.

PubMed: 22657089
DOI: 10.1021/BI300251R

実験手法

X-RAY DIFFRACTION (2.4 Å)