A Novel Integrated Way for Deciphering the Glycan Code for the FimH Lectin

Molecules

Clarisse Bridot¹  Ralf Blossey¹  MarcF. Lensink²  Eva-Maria Krammer³  Sabine Szunerits³  Tetiana Dumych³  Rostyslav Bilyy⁴  Julie Bouckaert⁵  SébastienG. Gouin⁵  Solomiya Paryzhak⁵ 

[1] Department of Medical Biology, Parasitology and Genetics, 79010 Lviv, Ukraine;Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR 6230 Centre National de la Recherche Scientifique, Université Nantes, 44322 Nantes, France;;Danylo Halytsky Lviv National Medical University, Department of Histology, Cytology and Embryology &Univ. Lille, CNRS, Centrale Lille, ISEN, Univ. Valenciennes, UMR 8520-IEMN, F-59000 Lille, France;University of Lille, CNRS UMR8576 UGSF, Institute for Structural and Functional Glycobiology, F-59000 Lille, France;

关键词: Manα1,3Man;    Manα1,2Man;    FimH;    binding mode;    Enzyme-Linked LectinoSorbent assay;    microcalorimetry;    molecular dynamics;    thermodynamics;    entropy;    high-mannose N-glycan;   

DOI  :  10.3390/molecules23112794

来源: DOAJ

【 摘 要 】

The fimbrial lectin FimH from uro- and enteropathogenic Escherichia coli binds with nanomolar affinity to oligomannose glycans exposing Manα1,3Man dimannosides at their non-reducing end, but only with micromolar affinities to Manα1,2Man dimannosides. These two dimannoses play a significantly distinct role in infection by E. coli. Manα1,2Man has been described early on as shielding the (Manα1,3Man) glycan that is more relevant to strong bacterial adhesion and invasion. We quantified the binding of the two dimannoses (Manα1,2Man and Manα1,3Man to FimH using ELLSA and isothermal microcalorimetry and calculated probabilities of binding modes using molecular dynamics simulations. Our experimentally and computationally determined binding energies confirm a higher affinity of FimH towards the dimannose Manα1,3Man. Manα1,2Man displays a much lower binding enthalpy combined with a high entropic gain. Most remarkably, our molecular dynamics simulations indicate that Manα1,2Man cannot easily take its major conformer from water into the FimH binding site and that FimH is interacting with two very different conformers of Manα1,2Man that occupy 42% and 28% respectively of conformational space. The finding that Manα1,2Man binding to FimH is unstable agrees with the earlier suggestion that E. coli may use the Manα1,2Man epitope for transient tethering along cell surfaces in order to enhance dispersion of the infection.

【 授权许可】

Unknown