5awd: Difference between revisions
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==Crystal structure of human TLR8 in complex with N1-4-aminomethylbenzyl (IMDQ)== | |||
<StructureSection load='5awd' size='340' side='right'caption='[[5awd]], [[Resolution|resolution]] 2.05Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5awd]] is a 1 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=5AWD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5AWD FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.05Å</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=IDQ:1-[[4-(AMINOMETHYL)PHENYL]METHYL]-2-BUTYL-IMIDAZO[4,5-C]QUINOLIN-4-AMINE'>IDQ</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</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=5awd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5awd OCA], [https://pdbe.org/5awd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5awd RCSB], [https://www.ebi.ac.uk/pdbsum/5awd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5awd ProSAT]</span></td></tr> | |||
</table> | |||
== 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> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5awd" style="background-color:#fffaf0;"></div> | ||
[[Category: Shimizu | |||
[[Category: | ==See Also== | ||
*[[Toll-like Receptor 3D structures|Toll-like Receptor 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Ohto U]] | |||
[[Category: Shimizu T]] | |||
[[Category: Tanji H]] | |||
Latest revision as of 13:35, 30 October 2024
Crystal structure of human TLR8 in complex with N1-4-aminomethylbenzyl (IMDQ)Crystal structure of human TLR8 in complex with N1-4-aminomethylbenzyl (IMDQ)
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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