Immunoglobulin G (IgG) antibodies are one such example of glycoproteins that exhibit considerable glycoform diversity. This makes precision targeting of protein glycoforms an attractive platform for clinical diagnostics and therapeutics. In this vein, some glycoforms may be markers of specific disease states or differentially contribute to protective and pathogenic mechanisms, as has been documented extensively 1, 2, 3, 4, 5, 6, 7, 8, 9. Although related protein glycoforms have an identical amino acid backbone and may differ by only a single sugar residue, they can exhibit vastly different biological functions. On glycoproteins, glycans often exist as structurally similar but distinct motifs, known as glycoforms. They are present in all living cells, decorating proteins, lipids, and even nucleic acids, where they help to define molecular functions. Glycans are ubiquitous and play essential roles throughout biology. Based on this structure, we designed X0 fusion constructs that disrupt pathogenic afucosylated IgG1-FcγRIIIa interactions and rescue mice in a model of dengue virus infection. Upon binding, the elongated CDR3 loop of X0 undergoes a conformational shift to access the buried N-glycan and acts as a ‘glycan sensor’, forming hydrogen bonds with the afucosylated IgG N-glycan that would otherwise be sterically hindered by the presence of a core fucose residue. We previously reported synthetic nanobodies that distinguish IgG glycoforms. Here, we present the structure of one such nanobody, X0, in complex with the Fc fragment of afucosylated IgG1. The variable construction of this glycan structure leads to highly-related, but non-equivalent glycoproteins known as glycoforms. This glycan contributes to the structural organization of the Fc domain and determines its specificity for Fcγ receptors, thereby dictating distinct cellular responses. Immunoglobulin G (IgG) antibodies contain a complex N-glycan embedded in the hydrophobic pocket between its heavy chain protomers.
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