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PDBsum entry 2df3
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Cell adhesion
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PDB id
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2df3
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References listed in PDB file
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Key reference
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Title
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The structure of siglec-7 in complex with sialosides: leads for rational structure-Based inhibitor design.
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Authors
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H.Attrill,
H.Takazawa,
S.Witt,
S.Kelm,
R.Isecke,
R.Brossmer,
T.Ando,
H.Ishida,
M.Kiso,
P.R.Crocker,
D.M.Van aalten.
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Ref.
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Biochem J, 2006,
397,
271-278.
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PubMed id
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Abstract
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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.
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