Abstract
Glycosylation is an important post-translational modification that affects a wide variety of physiological functions. DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) is a protein expressed in antigen-presenting cells that recognizes a variety of glycan epitopes. Until now, the binding of DC-SIGN to SARS-CoV-2 Spike glycoprotein has been reported in various articles and is regarded to be a factor in systemic infection and cytokine storm. The mechanism of DC-SIGN recognition offers an alternative method for discovering new medication for COVID-19 treatment. Here, we discovered three potential pockets that hold different glycan epitopes by performing molecular dynamics simulations of previously reported oligosaccharides. The “EPN” motif, “NDD” motif, and Glu354 form the most critical pocket, which is known as the Core site. We proposed that the type of glycan epitopes, rather than the precise amino acid sequence, determines the recognition. Furthermore, we deduced that oligosaccharides could occupy an additional site, which adds to their higher affinity than monosaccharides. Based on our findings and previously described glycoforms on the SARS-CoV-2 Spike, we predicted the potential glycan epitopes for DC-SIGN. It suggested that glycan epitopes could be recognized at multiple sites, not just Asn234, Asn149 and Asn343. Subsequently, we found that Saikosaponin A and Liquiritin, two plant glycosides, were promising DC-SIGN antagonists in silico.
Highlights
Introduction published maps and institutional affilGlycosylation is a common post-translational modification that affects a wide range of physiological activities
One Glycan-binding proteins (GBP) is DC-SIGN, which belongs to the C-type lectin superfamily
We discovered three potential pockets that hold different glycan epitopes by performing molecular dynamics simulations of previously reported oligosaccharides
Summary
The GLYCAM website (https://dev.glycam.org/cb/, accessed on 15 July 2021) is used to construct the structure of certain commonly used glycosides [35]. A total of five molecular oligosaccharide chain structures were constructed, namely Manα1,2[Manα1,6]Man; Manα1,2Manα1,2Man; Manα1,2Manα1,3Man; Glcα1,3Glcα1,3Glc; and GlcNAcβ1,4[Fucα1,6]. GlcNAc. The remaining oligosaccharides were synthesized using the crystal structure of the existing DC-SIGN complex (PDB: 1K9I, 1SL4, 1SL5, 2IT5, 2IT6). The LigPrep module of the Schrodinger suite (Schrödinger release 2020-4: Schrödinger, LLC, New York, NY, USA) was used to complete the glycoside structure preparation before the screening. The ligand was imported to the Schrodinger workspace and the ligand’s 3D structure was generated by adding hydrogen atoms, eliminating salt, and ionizing at pH 7 ± 2. A maximum of 32 stereoisomers was set
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