2g5r
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Crystal structure of Siglec-7 in complex with methyl-9-(aminooxalyl-amino)-9-deoxyNeu5Ac (oxamido-Neu5Ac)
OverviewOverview
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, [alpha(2,3)/alpha(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 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 (N-acetylneuraminic acid) as a basic scaffold. A, co-crystal of siglec-7 in complex with the sialoside inhibitor, oxamido-Neu5Ac [methyl alpha-9-(amino-oxalyl-amino)-9-deoxy-Neu5Ac] and, inhibition data for the sialosides gives clear leads for future inhibitor, design.
About this StructureAbout this Structure
2G5R is a Single protein structure of sequence from Homo sapiens with NAG, NXD and CYS as ligands. Full crystallographic information is available from OCA.
ReferenceReference
The structure of siglec-7 in complex with sialosides: leads for rational structure-based inhibitor design., Attrill H, Takazawa H, Witt S, Kelm S, Isecke R, Brossmer R, Ando T, Ishida H, Kiso M, Crocker PR, van Aalten DM, Biochem J. 2006 Jul 15;397(2):271-8. PMID:16623661
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