|
|
| (3 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| | | | |
| | ==Crystal structure of human TLR8 in complex with DS-877== | | ==Crystal structure of human TLR8 in complex with DS-877== |
| - | <StructureSection load='3wn4' size='340' side='right' caption='[[3wn4]], [[Resolution|resolution]] 1.81Å' scene=''> | + | <StructureSection load='3wn4' size='340' side='right'caption='[[3wn4]], [[Resolution|resolution]] 1.81Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3wn4]] 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=3WN4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3WN4 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3wn4]] 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=3WN4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3WN4 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=D87:2-BUTYLFURO[2,3-C]QUINOLIN-4-AMINE'>D87</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene></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]] 1.81Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TLR8, UNQ249/PRO286 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=D87:2-BUTYLFURO[2,3-C]QUINOLIN-4-AMINE'>D87</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3wn4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wn4 OCA], [http://pdbe.org/3wn4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3wn4 RCSB], [http://www.ebi.ac.uk/pdbsum/3wn4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3wn4 ProSAT]</span></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=3wn4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wn4 OCA], [https://pdbe.org/3wn4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3wn4 RCSB], [https://www.ebi.ac.uk/pdbsum/3wn4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3wn4 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 21: |
Line 21: |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Toll-like Receptors|Toll-like Receptors]] | + | *[[Toll-like Receptor 3D structures|Toll-like Receptor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Ohto, U]] | + | [[Category: Large Structures]] |
| - | [[Category: Shimizu, T]] | + | [[Category: Ohto U]] |
| - | [[Category: Tanji, H]] | + | [[Category: Shimizu T]] |
| - | [[Category: Antiviral-antitumor drug binding]] | + | [[Category: Tanji H]] |
| - | [[Category: Glycosylation]]
| + | |
| - | [[Category: Immune system]]
| + | |
| - | [[Category: Innate immunity]]
| + | |
| - | [[Category: Leucine rich repeat]]
| + | |
| - | [[Category: Rna]]
| + | |
| - | [[Category: Rna recognition]]
| + | |
| - | [[Category: Ssrnar]]
| + | |
| - | [[Category: Structure-based ligand design]]
| + | |
| - | [[Category: Tlr8-specific agonist]]
| + | |
| - | [[Category: Vaccine adjuvant]]
| + | |
| Structural highlights
Function
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.[1]
Publication Abstract from PubMed
Toll-like receptor (TLR)-8 agonists activate adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds might be promising candidate vaccine adjuvants. Recently, a C2-butyl furo[2,3-c]quinoline was reported with purely TLR8 agonistic activity. This compound was successfully co-crystallized with the human TLR8 ectodomain, and the co-crystal structure revealed ligand-induced reorganization of the binding pocket of TLR8. The loss of a key hydrogen bond between the oxygen atom of the furanyl ring of the agonist and Thr 574 in TLR8 suggested that the furan ring is dispensable. Employing a disconnection strategy, 3- and 4-substituted aminoquinolines were investigated. Focused structure-based ligand design studies led to the identification of 3-pentyl-quinoline-2-amine as a novel, structurally simple, and highly potent human TLR8-specific agonist (EC50 =0.2 muM). Preliminary evaluation of this compound in ex vivo human blood assay systems revealed that it retains prominent cytokine-inducing activity. Together, these results indicate the suitability of this compound as a novel vaccine adjuvant, warranting further investigation.
Structure-Based Design of Novel Human Toll-like Receptor 8 Agonists.,Kokatla HP, Sil D, Tanji H, Ohto U, Malladi SS, Fox LM, Shimizu T, David SA ChemMedChem. 2014 Jan 28. doi: 10.1002/cmdc.201300573. PMID:24474703[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Doyle SL, Jefferies CA, Feighery C, O'Neill LA. Signaling by Toll-like receptors 8 and 9 requires Bruton's tyrosine kinase. J Biol Chem. 2007 Dec 21;282(51):36953-60. Epub 2007 Oct 11. PMID:17932028 doi:10.1074/jbc.M707682200
- ↑ Kokatla HP, Sil D, Tanji H, Ohto U, Malladi SS, Fox LM, Shimizu T, David SA. Structure-Based Design of Novel Human Toll-like Receptor 8 Agonists. ChemMedChem. 2014 Jan 28. doi: 10.1002/cmdc.201300573. PMID:24474703 doi:http://dx.doi.org/10.1002/cmdc.201300573
|
