Calcium Competitive Inhibition of Langerin by Thiazolopyrimidinones

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.