7nl6: Difference between revisions
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==Crystal Structure of DC-SIGN in complex with a triazole-based glycomimetic ligand== | ==Crystal Structure of DC-SIGN in complex with a triazole-based glycomimetic ligand== | ||
<StructureSection load='7nl6' size='340' side='right'caption='[[7nl6]]' scene=''> | <StructureSection load='7nl6' size='340' side='right'caption='[[7nl6]], [[Resolution|resolution]] 2.20Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NL6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NL6 FirstGlance]. <br> | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NL6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NL6 FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7nl6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nl6 OCA], [https://pdbe.org/7nl6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nl6 RCSB], [https://www.ebi.ac.uk/pdbsum/7nl6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nl6 ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=UH8:Methyl+2-deoxy-2-(4-(pyridine-3-yl))-1,2,3-triazol-1-yl)-alpha-D-mannopyranoside'>UH8</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7nl6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nl6 OCA], [https://pdbe.org/7nl6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nl6 RCSB], [https://www.ebi.ac.uk/pdbsum/7nl6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nl6 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The C-type lectin receptor DC-SIGN is a pattern recognition receptor expressed on macrophages and dendritic cells. It has been identified as a promiscuous entry receptor for many pathogens, including epidemic and pandemic viruses such as SARS-CoV-2, Ebola virus, and HIV-1. In the context of the recent SARS-CoV-2 pandemic, DC-SIGN-mediated virus dissemination and stimulation of innate immune responses has been implicated as a potential factor in the development of severe COVID-19. Inhibition of virus binding to DC-SIGN, thus, represents an attractive host-directed strategy to attenuate overshooting innate immune responses and prevent the progression of the disease. In this study, we report on the discovery of a new class of potent glycomimetic DC-SIGN antagonists from a focused library of triazole-based mannose analogues. Structure-based optimization of an initial screening hit yielded a glycomimetic ligand with a more than 100-fold improved binding affinity compared to methyl alpha-d-mannopyranoside. Analysis of binding thermodynamics revealed an enthalpy-driven improvement of binding affinity that was enabled by hydrophobic interactions with a loop region adjacent to the binding site and displacement of a conserved water molecule. The identified ligand was employed for the synthesis of multivalent glycopolymers that were able to inhibit SARS-CoV-2 spike glycoprotein binding to DC-SIGN-expressing cells, as well as DC-SIGN-mediated trans-infection of ACE2(+) cells by SARS-CoV-2 spike protein-expressing viruses, in nanomolar concentrations. The identified glycomimetic ligands reported here open promising perspectives for the development of highly potent and fully selective DC-SIGN-targeted therapeutics for a broad spectrum of viral infections. | |||
Sweet Drugs for Bad Bugs: A Glycomimetic Strategy against the DC-SIGN-Mediated Dissemination of SARS-CoV-2.,Cramer J, Lakkaichi A, Aliu B, Jakob RP, Klein S, Cattaneo I, Jiang X, Rabbani S, Schwardt O, Zimmer G, Ciancaglini M, Abreu Mota T, Maier T, Ernst B J Am Chem Soc. 2021 Oct 15. doi: 10.1021/jacs.1c06778. PMID:34652144<ref>PMID:34652144</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7nl6" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
