2xr6
From Proteopedia
(Difference between revisions)
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| - | == | + | ==Crystal structure of the complex of the carbohydrate recognition domain of human DC-SIGN with pseudo trimannoside mimic.== |
<StructureSection load='2xr6' size='340' side='right' caption='[[2xr6]], [[Resolution|resolution]] 1.35Å' scene=''> | <StructureSection load='2xr6' size='340' side='right' caption='[[2xr6]], [[Resolution|resolution]] 1.35Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[2xr6]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/ | + | <table><tr><td colspan='2'>[[2xr6]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2XR6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2XR6 FirstGlance]. <br> |
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=07B:DIMETHYL+(1S,2S,4S,5S)-4,5-DIHYDROXYCYCLOHEXANE-1,2-DICARBOXYLATE'>07B</scene>, <scene name='pdbligand=AE9:2-AZIDOETHANOL'>AE9</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene><br> | </td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=07B:DIMETHYL+(1S,2S,4S,5S)-4,5-DIHYDROXYCYCLOHEXANE-1,2-DICARBOXYLATE'>07B</scene>, <scene name='pdbligand=AE9:2-AZIDOETHANOL'>AE9</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene><br> | ||
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2b6b|2b6b]], [[1sl4|1sl4]], [[1k9i|1k9i]], [[1sl5|1sl5]], [[2xr5|2xr5]]</td></tr> | <tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2b6b|2b6b]], [[1sl4|1sl4]], [[1k9i|1k9i]], [[1sl5|1sl5]], [[2xr5|2xr5]]</td></tr> | ||
| - | <tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </span></td></tr> | ||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2xr6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xr6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2xr6 RCSB], [http://www.ebi.ac.uk/pdbsum/2xr6 PDBsum]</span></td></tr> | <tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2xr6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xr6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2xr6 RCSB], [http://www.ebi.ac.uk/pdbsum/2xr6 PDBsum]</span></td></tr> | ||
<table> | <table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | DC-SIGN is a dendritic cell-specific C-type lectin receptor that recognizes highly glycosylated ligands expressed on the surface of various pathogens. This receptor plays an important role in the early stages of many viral infections, including HIV, which makes it an interesting therapeutic target. Glycomimetic compounds are good drug candidates for DC-SIGN inhibition due to their high solubility, resistance to glycosidases, and nontoxicity. We studied the structural properties of the interaction of the tetrameric DC-SIGN extracellular domain (ECD), with two glycomimetic antagonists, a pseudomannobioside (1) and a linear pseudomannotrioside (2). Though the inhibitory potency of 2, as measured by SPR competition experiments, was 1 order of magnitude higher than that of 1, crystal structures of the complexes within the DC-SIGN carbohydrate recognition domain showed the same binding mode for both compounds. Moreover, when conjugated to multivalent scaffolds, the inhibitory potencies of these compounds became uniform. Combining isothermal titration microcalorimetry, analytical ultracentrifugation, and dynamic light scattering techniques to study DC-SIGN ECD interaction with these glycomimetics revealed that 2 is able, without any multivalent presentation, to cluster DC-SIGN tetramers leading to an artificially overestimated inhibitory potency. The use of multivalent scaffolds presenting 1 or 2 in HIV trans-infection inhibition assay confirms the loss of potency of 2 upon conjugation and the equal efficacy of chemically simpler compound 1. This study documents a unique case where, among two active compounds chemically derived, the compound with the lower apparent activity is the optimal lead for further drug development. | ||
| + | |||
| + | Unique DC-SIGN Clustering Activity of a Small Glycomimetic: A Lesson for Ligand Design.,Sutkeviciute I, Thepaut M, Sattin S, Berzi A, McGeagh J, Grudinin S, Weiser J, Le Roy A, Reina JJ, Rojo J, Clerici M, Bernardi A, Ebel C, Fieschi F ACS Chem Biol. 2014 May 6. PMID:24749535<ref>PMID:24749535</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: | + | [[Category: Human]] |
[[Category: Bernardi, A.]] | [[Category: Bernardi, A.]] | ||
[[Category: Fieschi, F.]] | [[Category: Fieschi, F.]] | ||
Revision as of 06:22, 30 July 2014
Crystal structure of the complex of the carbohydrate recognition domain of human DC-SIGN with pseudo trimannoside mimic.
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