Abstact

C-Type lectins are a large family of carbohydrate-binding proteins. Langerin is a member of this family and is expressed by Langerhans cells, involved in pathogen recognition and innate immune activation, making it a target for small-molecule modulation in immunology and infectious diseases. We previously identified thiazolopyrimidinones as a series of allosteric inhibitors, but the underlying mechanism remained unclear. In this study, 43Ca NMR demonstrated that these fragments induce Ca2+ release from the receptor. Our ITC data suggested a competitive relationship between inhibitors and Ca2+, which was further validated by 19F NMR spectroscopy showing inhibition of carbohydrate binding. Surprisingly, the fragment binding site was found to be located beneath the long loop, which supports the dynamic nature of the long loop being highly Ca2+ dependent. Our findings provide insight into the novel Ca2+-competitive inhibitory mechanism of murine langerin and are the first report on such an inhibitory mechanism for a C-type lectin.