The structure of siglec-7 in complex with sialosides: leads for rational structure-based inhibitor design

Helen Attrill, Hirokazu Takazawa, Simone Witt, Soerge Kelm, Rainier Isecke, Reinhard Brossmer, Takayuki Ando, Hideharu Ishida, Makoto Kiso, Paul R. Crocker, Daan M. F. van Aalten

    Research output: Contribution to journalArticlepeer-review

    55 Citations (Scopus)

    Abstract

    Siglecs (sialic acid binding Ig-like lectins) are transmembrane receptors for sialylated glycoconjugates that modulate cellular interactions and signalling events in the haematopoietic, 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 desired for the detection of masked and unmasked forms of siglecs, to aid in dissection of signalling pathways and as tools to investigate siglecs as potential therapeutic targets. As a first step towards this end, we present the crystal structure of siglec-7 in complex with a sialylated ligand, the ganglioside analogue DSLc4 [a(2,3)/a(2,6) disialyl lactotetraosyl 2-(trimethylsilyl)ethyl], which allows for a 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 Lys 131, a residue that changes conformation upon sialic acid binding. Differences between the binding sites of siglec family members were then exploited using a-methyl Neu5Ac (N-acetylneuraminic acid) as a basic scaffold. A co-crystal of siglec-7 in complex with the sialoside inhibitor, oxamido-Neu5Ac [methyl a-9-(amino-oxalyl-amino)-9-deoxy-Neu5Ac] and inhibition data for the sialosides gives clear leads for future inhibitor design.

    Original languageEnglish
    Pages (from-to)271-278
    Number of pages8
    JournalBiochemical Journal
    Volume397
    Issue number2
    DOIs
    Publication statusPublished - 2006

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