4avk Citations

The tyrosine gate as a potential entropic lever in the receptor-binding site of the bacterial adhesin FimH.

Biochemistry 51 4790-9 (2012)
Related entries: 4auu, 4auy, 4av0, 4av4, 4av5, 4avh, 4avi, 4avj

Cited: 37 times
EuropePMC logo PMID: 22657089

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.

Reviews citing this publication (10)

  1. FimH and Anti-Adhesive Therapeutics: A Disarming Strategy Against Uropathogens. Sarshar M, Behzadi P, Ambrosi C, Zagaglia C, Palamara AT, Scribano D. Antibiotics (Basel) 9 E397 (2020)
  2. Rational design strategies for FimH antagonists: new drugs on the horizon for urinary tract infection and Crohn's disease. Mydock-McGrane LK, Hannan TJ, Janetka JW. Expert Opin Drug Discov 12 711-731 (2017)
  3. Biogenesis and adhesion of type 1 and P pili. Lillington J, Geibel S, Waksman G. Biochim Biophys Acta 1840 2783-2793 (2014)
  4. Mannose-derived FimH antagonists: a promising anti-virulence therapeutic strategy for urinary tract infections and Crohn's disease. Mydock-McGrane LK, Cusumano ZT, Janetka JW. Expert Opin Ther Pat 26 175-197 (2016)
  5. Glycomimetics for the inhibition and modulation of lectins. Leusmann S, Ménová P, Shanin E, Titz A, Rademacher C. Chem Soc Rev 52 3663-3740 (2023)
  6. Chemical attenuation of pilus function and assembly in Gram-negative bacteria. Lo AW, Moonens K, Remaut H. Curr Opin Microbiol 16 85-92 (2013)
  7. Bacterial surface appendages as targets for novel antibacterial therapeutics. Steadman D, Lo A, Waksman G, Remaut H. Future Microbiol 9 887-900 (2014)
  8. Developments in Mannose-Based Treatments for Uropathogenic Escherichia coli-Induced Urinary Tract Infections. Hatton NE, Baumann CG, Fascione MA. Chembiochem 22 613-629 (2021)
  9. Targeting Dynamical Binding Processes in the Design of Non-Antibiotic Anti-Adhesives by Molecular Simulation-The Example of FimH. Krammer EM, de Ruyck J, Roos G, Bouckaert J, Lensink MF. Molecules 23 E1641 (2018)
  10. Neutralizing Antibodies Against Allosteric Proteins: Insights From a Bacterial Adhesin. Sokurenko EV, Tchesnokova V, Interlandi G, Klevit R, Thomas WE. J Mol Biol 434 167717 (2022)

Articles citing this publication (27)