Breaking the limits in understanding glycan recognition by NMR

Place: conference room, IMDEA Nanociencia.

Abstract: 

Molecular recognition by specific targets is at the heart of the life processes.  Carbohydrates (glycans, saccharides, sugars), prevalent on mammalian cells and in the extracellular matrix, collectively form the glycocalyx, impacting physical properties, regulating protein function, and acting as ligands for lectins (glycan-binding proteins). Indeed, dysregulation of glycosyltransferases results in tumor-associated carbohydrate antigens (TACAs), unique to tumor cells. While TACAs are recognized therapeutic targets, their low immunogenicity is a challenge for T-cell-dependent immune responses, crucial for cancer therapy. TACAs play a key role in modulating immune responses within the tumor microenvironment through interactions with lectins. Similar interactions are observed in bacterial and viral-mediated infectious events. Therefore, the interactions between lectins, enzymes, antibodies and glycans mediate a broad range of biological activities, from fertilization and tissue maturation to pathological processes. In this context, the elucidation of the mechanisms that govern how sugars are accommodated in the binding sites of these receptors is currently a topic of interest. Thus, unravelling the structural, dynamic, and conformational factors that rule the interactions of these molecules is of paramount interest.

Solution NMR is unique in providing stereochemical, conformational, and dynamic information. Given the inherent flexibility and dynamic properties of glycans, we use NMR as key tool for deducing, at atomic resolution, molecular recognition events in which glycans are involved. Together with state-of-the-art NMR, we employ a combination of diverse and synergic methodologies, including chemical synthesis, protein biochemistry and molecular biology, biophysics (ITC, BLI), molecular modelling, and structural biology techniques (X-Ray crystallography and CryoEM). In this way, we investigate the interactions of glycans related to immune responses, from cancer to bacterial and viral infections.

This presentation focuses on the application of our NMR methodology, both from the ligand and receptor’s perspective, to study molecular recognition processes between receptors of biomedical interest and glycans. As recent examples, key details of glycan recognition by these receptors will be shown, with special emphasis in the interactions of the human blood antigens with galectins, of sialoglycans with Siglecs, and of the spike glycoprotein of SARS CoV-2 with human immune lectins and cell glycans.^1-7

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