Unraveling Sugar Binding Modes to DC-SIGN by Employing Fluorinated Carbohydrates

Molecules. 2019 Jun 25;24(12):2337. doi: 10.3390/molecules24122337.

Abstract

A fluorine nuclear magnetic resonance (19F-NMR)-based method is employed to assess the binding preferences and interaction details of a library of synthetic fluorinated monosaccharides towards dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN), a lectin of biomedical interest, which is involved in different viral infections, including HIV and Ebola, and is able to recognize a variety of self- and non-self-glycans. The strategy employed allows not only screening of a mixture of compounds, but also obtaining valuable information on the specific sugar-protein interactions. The analysis of the data demonstrates that monosaccharides Fuc, Man, Glc, and Gal are able to bind DC-SIGN, although with decreasing affinity. Moreover, a new binding mode between Man moieties and DC-SIGN, which might have biological implications, is also detected for the first time. The combination of the 19F with standard proton saturation transfer difference (1H-STD-NMR) data, assisted by molecular dynamics (MD) simulations, permits us to successfully define this new binding epitope, where Man coordinates a Ca2+ ion of the lectin carbohydrate recognition domain (CRD) through the axial OH-2 and equatorial OH-3 groups, thus mimicking the Fuc/DC-SIGN binding architecture.

Keywords: 19F-NMR; C-type lectins; DC-SIGN; NMR; fluorinated sugars; glycomimetics; lectin; molecular dynamics; molecular recognition; screening.

MeSH terms

  • Cell Adhesion Molecules / chemistry*
  • Cell Adhesion Molecules / metabolism
  • Halogenation
  • Lectins, C-Type / chemistry*
  • Lectins, C-Type / metabolism
  • Models, Molecular
  • Molecular Conformation
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Binding
  • Receptors, Cell Surface / chemistry*
  • Receptors, Cell Surface / metabolism
  • Structure-Activity Relationship
  • Sugars / chemistry*
  • Sugars / metabolism

Substances

  • Cell Adhesion Molecules
  • DC-specific ICAM-3 grabbing nonintegrin
  • Lectins, C-Type
  • Receptors, Cell Surface
  • Sugars