The structure of siglec-7 in complex with sialosides: leads for rational structure-based inhibitor design
Résumé
Siglecs are transmembrane receptors for sialylated glycoconjugates and modulate cellular interactions and signaling events in the hematopoietic, immune and nervous systems. Siglec-7 is a structural prototype for the recently described family of immune inhibitory CD33-related siglecs and is predominantly expressed on natural killer cells and monocytes as well as subsets of CD8 T cells. Siglec-specific inhibitors are desirable for detection of masked and unmasked forms of siglecs, to aid in dissection of signaling pathways and as tools to investigate siglecs as potential therapeutic targets. As a first step towards this, we present a crystal structure of Siglec-7 in complex with a sialylated ligand, the ganglioside analogue {alpha}(2,3)/{alpha}(2,6) disialyl lactotetraosyl 2-(trimethylsilyl)ethyl (DSLc4), allowing the detailed description of the binding site required for structure-guided inhibitor design. Mutagenesis and binding assays were used to demonstrate a key structural role for Lys131, a residue that changes conformation upon sialic acid binding. Differences between the binding sites of siglec family members were then exploited using {alpha}-methyl Neu5Ac as a basic scaffold. A co-crystal of Siglec-7 in complex with the sialoside inhibitor methyl {alpha}-9-(aminooxalyl-amino)-9-deoxyNeu5Ac and inhibition data of sialosides gives clear leads for future inhibitor design.
Origine : Fichiers produits par l'(les) auteur(s)
Loading...