MPI-NAT Seminar: Breaking the limits in understanding glycan recognition by NMR

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. 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 conformation and dynamics of glycans and molecular recognition events with their receptors of biomedical interest. Recent examples will be shown, including new NMR avenues to unravel the interactions of glycans on intact glycoproteins and on cell surfaces.1-7

References
1. Unione et al., ACS Cent Sci 2019, 5, 1554; Curr Opin Struct Biol 2021, 68, 9; Angew Chem Int Ed, 2022, 61: e202201432; Østerlid et al., Angew Chem Int Ed. 2025, 64, e202511378.
2. Gimeno et al., Curr. Opin. Struct. Biol. 2020, 62, 22; Angulo, Jiménez-Barbero et al., Prog NMR Spectrosc. 2024, 144, 97. Quintana et al., J Biol Chem. 2024, 300, 107577; Glycobiology. 2024, 34:cwae002.
3. Lenza et al., Angew Chem Int Ed. 2020, 59, 23763; JACS Au. 2023, 3, 204; Nat Comm. 2023, 14, 3496
4. Moure et al., Angew Chem Int Ed 2021, 60, 18777–82. Atxabal et al., Chem Sci 2024, 15, 10612
5. Bertuzzi et al., ACS Chem Sci. 2022, 8, 1415; Chem Eur J. 2025, 31:e202403102.
6. Wang et al., J Am Chem Soc 2023, 145, 14052; Angew Chem Int Ed. 2023, 62: e202211940.
7. Fittolani et al., Nat Chem. 2023, 15, 1461; Yadav et al J Am Chem Soc 2024, 146, 6369.