2df3
From Proteopedia
(New page: 200px<br /> <applet load="2df3" size="450" color="white" frame="true" align="right" spinBox="true" caption="2df3, resolution 1.900Å" /> '''The structure of S...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:2df3.gif|left|200px]]<br /> | + | [[Image:2df3.gif|left|200px]]<br /><applet load="2df3" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2df3" size=" | + | |
caption="2df3, resolution 1.900Å" /> | caption="2df3, resolution 1.900Å" /> | ||
'''The structure of Siglec-7 in complex with alpha(2,3)/alpha(2,6) disialyl lactotetraosyl 2-(trimethylsilyl)ethyl'''<br /> | '''The structure of Siglec-7 in complex with alpha(2,3)/alpha(2,6) disialyl lactotetraosyl 2-(trimethylsilyl)ethyl'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Siglecs (sialic acid binding Ig-like lectins) are transmembrane receptors | + | 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 Structure== | ==About this Structure== | ||
| - | 2DF3 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NAG and CYS as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 2DF3 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NAG:'>NAG</scene> and <scene name='pdbligand=CYS:'>CYS</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2DF3 OCA]. |
==Reference== | ==Reference== | ||
| Line 21: | Line 20: | ||
[[Category: siglec]] | [[Category: siglec]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:58:08 2008'' |
Revision as of 14:58, 21 February 2008
|
The structure of Siglec-7 in complex with alpha(2,3)/alpha(2,6) disialyl lactotetraosyl 2-(trimethylsilyl)ethyl
Overview
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 Structure
2DF3 is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
Reference
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
Page seeded by OCA on Thu Feb 21 16:58:08 2008
Categories: Homo sapiens | Single protein | Attrill, H. | CYS | NAG | Ganglioside | Sialic acid | Siglec
