5awb: Difference between revisions
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==Crystal structure of human TLR8 in complex with N1-3-aminomethylbenzyl (meta-amine)== | ==Crystal structure of human TLR8 in complex with N1-3-aminomethylbenzyl (meta-amine)== | ||
<StructureSection load='5awb' size='340' side='right' caption='[[5awb]], [[Resolution|resolution]] 2.10Å' scene=''> | <StructureSection load='5awb' size='340' side='right' caption='[[5awb]], [[Resolution|resolution]] 2.10Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5awb]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AWB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AWB FirstGlance]. <br> | <table><tr><td colspan='2'>[[5awb]] 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=5AWB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AWB 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=M0A:1-[[3-(AMINOMETHYL)PHENYL]METHYL]-2-BUTYL-IMIDAZO[4,5-C]QUINOLIN-4-AMINE'>M0A</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | </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=M0A:1-[[3-(AMINOMETHYL)PHENYL]METHYL]-2-BUTYL-IMIDAZO[4,5-C]QUINOLIN-4-AMINE'>M0A</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5awa|5awa]], [[5awc|5awc]], [[5awd|5awd]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5awa|5awa]], [[5awc|5awc]], [[5awd|5awd]]</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=5awb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5awb OCA], [http://pdbe.org/5awb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5awb RCSB], [http://www.ebi.ac.uk/pdbsum/5awb PDBsum]</span></td></tr> | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TLR8 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5awb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5awb OCA], [http://pdbe.org/5awb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5awb RCSB], [http://www.ebi.ac.uk/pdbsum/5awb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5awb ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | == Function == | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Ohto, U]] | [[Category: Ohto, U]] | ||
[[Category: Shimizu, T]] | [[Category: Shimizu, T]] | ||
Revision as of 18:39, 16 November 2017
Crystal structure of human TLR8 in complex with N1-3-aminomethylbenzyl (meta-amine)Crystal structure of human TLR8 in complex with N1-3-aminomethylbenzyl (meta-amine)
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 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. References
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