5awc: Difference between revisions
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<StructureSection load='5awc' size='340' side='right'caption='[[5awc]], [[Resolution|resolution]] 2.50Å' scene=''> | <StructureSection load='5awc' size='340' side='right'caption='[[5awc]], [[Resolution|resolution]] 2.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5awc]] is a 4 chain structure with sequence from [ | <table><tr><td colspan='2'>[[5awc]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AWC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5AWC FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=M4D:5-(4-AZANYLBUTYL)-3-PENTYL-QUINOLIN-2-AMINE'>M4D</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=M4D:5-(4-AZANYLBUTYL)-3-PENTYL-QUINOLIN-2-AMINE'>M4D</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=5awc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5awc OCA], [https://pdbe.org/5awc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5awc RCSB], [https://www.ebi.ac.uk/pdbsum/5awc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5awc ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/TLR8_HUMAN TLR8_HUMAN] Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response.<ref>PMID:17932028</ref> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Human Toll-like receptor 8 (hTLR8) is expressed in myeloid dendritic cells, monocytes, and monocyte-derived dendritic cells. Engagement by TLR8 agonists evokes a distinct cytokine profile which favors the development of type 1 helper T cells. Crystal structures of the ectodomain of hTLR8 cocrystallized with two regioisomers of a dual TLR7/8-agonistic N1-substituted imidazoquinolines showed subtle differences in their interactions in the binding site of hTLR8. We hypothesized that the potency of a previously reported best-in-class pure TLR8 agonist, 3-pentylquinoline-2-amine, could be further enhanced by "designing in" functional groups that would mimic key intermolecular interactions that we had observed in the crystal structures. We performed a focused exploration of decorating the quinoline core with alkylamino groups at all possible positions. These studies have led to the identification of a novel TLR8 agonist that was approximately 20-fold more potent than the parent compound and displays prominent adjuvantic activity in a rabbit model of immunization. | |||
Structure-Based Design of Human TLR8-Specific Agonists with Augmented Potency and Adjuvanticity.,Beesu M, Caruso G, Salyer AC, Khetani KK, Sil D, Weerasinghe M, Tanji H, Ohto U, Shimizu T, David SA J Med Chem. 2015 Oct 8;58(19):7833-49. doi: 10.1021/acs.jmedchem.5b01087. Epub, 2015 Sep 22. PMID:26351878<ref>PMID:26351878</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5awc" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Toll-like | *[[Toll-like Receptor 3D structures|Toll-like Receptor 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Ohto | [[Category: Ohto U]] | ||
[[Category: Shimizu | [[Category: Shimizu T]] | ||
[[Category: Tanji | [[Category: Tanji H]] | ||
Revision as of 09:27, 31 May 2023
Crystal structure of human TLR8 in complex with MB-564Crystal structure of human TLR8 in complex with MB-564
Structural highlights
FunctionTLR8_HUMAN Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response.[1] Publication Abstract from PubMedHuman Toll-like receptor 8 (hTLR8) is expressed in myeloid dendritic cells, monocytes, and monocyte-derived dendritic cells. Engagement by TLR8 agonists evokes a distinct cytokine profile which favors the development of type 1 helper T cells. Crystal structures of the ectodomain of hTLR8 cocrystallized with two regioisomers of a dual TLR7/8-agonistic N1-substituted imidazoquinolines showed subtle differences in their interactions in the binding site of hTLR8. We hypothesized that the potency of a previously reported best-in-class pure TLR8 agonist, 3-pentylquinoline-2-amine, could be further enhanced by "designing in" functional groups that would mimic key intermolecular interactions that we had observed in the crystal structures. We performed a focused exploration of decorating the quinoline core with alkylamino groups at all possible positions. These studies have led to the identification of a novel TLR8 agonist that was approximately 20-fold more potent than the parent compound and displays prominent adjuvantic activity in a rabbit model of immunization. Structure-Based Design of Human TLR8-Specific Agonists with Augmented Potency and Adjuvanticity.,Beesu M, Caruso G, Salyer AC, Khetani KK, Sil D, Weerasinghe M, Tanji H, Ohto U, Shimizu T, David SA J Med Chem. 2015 Oct 8;58(19):7833-49. doi: 10.1021/acs.jmedchem.5b01087. Epub, 2015 Sep 22. PMID:26351878[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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