Secondary Sites of the C-type Lectin-Like Fold

C-type lectins are a large superfamily of proteins involved in a multitude of biological processes. In particular, their involvement in immunity and homeostasis has rendered them attractive targets for diverse therapeutic interventions. They share a characteristic C-type lectin-like domain whose adaptability enables them to bind a broad spectrum of ligands beyond the originally defined canonical Ca2+-dependent carbohydrate binding. Together with variable domain architecture and high-level conformational plasticity, this enables C-type lectins to meet diverse functional demands. Secondary sites provide another layer of regulation and are often intricately linked to functional diversity. Located remote from the canonical primary binding site, secondary sites can accommodate ligands with other physicochemical properties and alter protein dynamics, thus enhancing selectivity and enabling fine-tuning of the biological response. In this review, we outline the structural determinants allowing C-type lectins to perform a large variety of tasks and to accommodate the ligands associated with it. Using the six well-characterized Ca2+-dependent and Ca2+-independent C-type lectin receptors DC-SIGN, langerin, MGL, dectin-1, CLEC-2 and NKG2D as examples, we focus on the characteristics of non-canonical interactions and secondary sites and their potential use in drug discovery endeavors. C-type lectins, a large superfamily of proteins, are crucial in immunity and homeostasis. Their C-type lectin-like domain enables them to bind a wide range of ligands, including those not dependent on Ca2+ interactions. This adaptability is further enhanced by their variable domain architecture and conformational plasticity. Secondary binding sites, often located away from the primary site, contribute to the C-type lectin functional diversity by accommodating different ligands, thus offering potential for drug discovery by fine-tuning biological responses and increasing selectivity. image