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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2019-06, Vol.24 (12), p.2337
• Main Authors: Martínez, J Daniel, Valverde, Pablo, Delgado, Sandra, Romanò, Cecilia, Linclau, Bruno, Reichardt, Niels C, Oscarson, Stefan, Ardá, Ana, Jiménez-Barbero, Jesús, Cañada, F Javier
• Format: Article
• Language: English
• Subjects: 19F-NMR; Amino acid sequence; Amino acids; Binding sites; C-type lectins; Calcium; Calcium ions; Carbohydrates; Cell Adhesion Molecules - chemistry; Cell Adhesion Molecules - metabolism; DC-SIGN; DC-SIGN protein; fluorinated sugars; Fluorination; Fluorine; glycomimetics; Halogenation; Hydroxyl groups; lectin; Lectins; Lectins, C-Type - chemistry; Lectins, C-Type - metabolism; Libraries; Ligands; Models, Molecular; Molecular Conformation; molecular dynamics; molecular recognition; Monosaccharides; NMR; Nuclear Magnetic Resonance, Biomolecular; Preferences; Protein Binding; Receptors, Cell Surface - chemistry; Receptors, Cell Surface - metabolism; screening; Structure-Activity Relationship; Sugar; Sugars - chemistry; Sugars - metabolism
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules24122337

A fluorine nuclear magnetic resonance ( F-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 F with standard proton saturation transfer difference ( H-STD-NMR) data, assisted by molecular dynamics (MD) simulations, permits us to successfully define this new binding epitope, where Man coordinates a Ca 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.