Seminar

Deciphering the structural details of the interaction mode of human lectins with glycans

June Ereño, PhD

Glycans are a spectacularly diverse group of molecules that can be anchored to other biomolecules like proteins and lipids. Their variation among cells and species is central to why pathogens devastate certain host species but not others. Moreover, it helps to explain the “spillover” of certain infectious agents, like SARS-CoV-2 virus, from one species to another, leading to global pandemics. But glycans are also key to cellular behaviors such as the interactions between immune cells and cancer cells. The sialic acid-binding immunoglobulin-type of lectins (Siglecs) are receptors that recognize sialic acid-containing glycans. In the majority of the cases Siglecs are expressed on the surface of immune cells. Over the years, it has been shown that binding of sialylated glycans to Siglecs regulates immunological responses, and that any imbalance can trigger different pathologies, such as autoimmune diseases or cancer. For all this, different therapeutics have been developed that bind to Siglecs, either based on antibodies (including CAR-T and bispecific antibodies) or being smaller molecules. Here we have elucidated the binding mode of therapeutic antibodies (Abs) and glycans (natural and modified) to Siglecs-2, -8 and -15 using a combination of structural biology (X-ray crystallography and NMR) and biophysical techniques. Molecular characterization of the interactions between Siglecs and therapeutic Abs or glycans has helped us to better understand the mode of operation and specificity of these receptors, and will directly contribute to the development of novel therapeutic agents.