Crystal Structure of the Carbohydrate Recognition Domain of the Human Macrophage Galactose C-Type Lectin Bound to GalNAc and the Tumor-Associated Tn Antigen

The human macrophage galactose lectin (MGL) is an endocytic type II transmembrane receptor expressed on immature monocyte-derived dendritic cells and activated macrophages plays a role in modulating the immune system response to infections cancer. MGL contains extracellular calcium-dependent (C-type) carbohydrate recognition domain (CRD) that specifically binds terminal N-acetylgalactosamine glycan residues such as Tn sialyl-Tn antigens found tumor cells, well other N- O-glycans displayed certain viruses parasites. Even though specificity of known several binding glycoproteins have been identified, molecular basis for substrate has remained elusive due lack high-resolution structures. Here we present crystal structures CRD at near endosomal pH complexes, which reveal details interactions with natural ligand, GalNAc, cancer-associated Tn-Ser antigen, synthetic GalNAc mimetic ligand. Like asialoglycoprotein receptor, additional calcium atoms are contribute stabilization fold. structure provides preferential over prompted re-evaluation modes previously proposed solution. Saturation transfer difference nuclear magnetic resonance data acquired using interpreted indicate single mode Models MGL1 MGL2, mouse homologues MGL, explain how these proteins might recognize LewisX respectively.