7r53: Difference between revisions
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==Crystal structure of human TLR8 in complex with Compound 15== | ==Crystal structure of human TLR8 in complex with Compound 15== | ||
<StructureSection load='7r53' size='340' side='right'caption='[[7r53]]' scene=''> | <StructureSection load='7r53' size='340' side='right'caption='[[7r53]], [[Resolution|resolution]] 3.12Å' 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=7R53 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7R53 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7r53]] is a 2 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=7R53 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7R53 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=7r53 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7r53 OCA], [https://pdbe.org/7r53 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7r53 RCSB], [https://www.ebi.ac.uk/pdbsum/7r53 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7r53 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]] 3.121Å</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=I5N:5-cyclopropyl-6-(2,6-dimethylpyridin-4-yl)-~{N}-[(3~{R},4~{R})-3-fluoranylpiperidin-4-yl]-1~{H}-indazol-3-amine'>I5N</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=7r53 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7r53 OCA], [https://pdbe.org/7r53 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7r53 RCSB], [https://www.ebi.ac.uk/pdbsum/7r53 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7r53 ProSAT]</span></td></tr> | |||
</table> | </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 == | |||
Inappropriate activation of TLR7 and TLR8 is linked to several autoimmune diseases, such as lupus erythematosus. Here we report on the efficient structure-based optimization of the inhibition of TLR8, starting from a co-crystal structure of a small screening hit. Further optimization of the physicochemical properties for cellular potency and expansion of the structure-activity relationship for dual potency finally resulted in a highly potent TLR7/8 antagonist with demonstrated in vivo efficacy after oral dosing. | |||
Structure-Based Optimization of a Fragment-like TLR8 Binding Screening Hit to an In Vivo Efficacious TLR7/8 Antagonist.,Betschart C, Faller M, Zink F, Hemmig R, Blank J, Vangrevelinghe E, Bourrel M, Glatthar R, Behnke D, Barker K, Heizmann A, Angst D, Nimsgern P, Jacquier S, Junt T, Zipfel G, Ruzzante G, Loetscher P, Limonta S, Hawtin S, Andre CB, Boulay T, Feifel R, Knoepfel T ACS Med Chem Lett. 2022 Mar 10;13(4):658-664. doi:, 10.1021/acsmedchemlett.1c00696. eCollection 2022 Apr 14. PMID:35450354<ref>PMID:35450354</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7r53" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Toll-like Receptor 3D structures|Toll-like Receptor 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Faller M]] | [[Category: Faller M]] | ||
[[Category: Zink F]] | [[Category: Zink F]] | ||
Latest revision as of 13:26, 1 February 2024
Crystal structure of human TLR8 in complex with Compound 15
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