View source for 8pfi


==Crystal structure of human TLR8 in complex with compound 34==
<StructureSection load='8pfi' size='340' side='right'caption='[[8pfi]], [[Resolution|resolution]] 2.79&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8pfi]] 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=8PFI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8PFI 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]] 2.785&#8491;</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=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=YHG:(3~{S})-~{N}-[4-[[5-(1,6-dimethylpyrazolo[3,4-b]pyridin-4-yl)-3-methyl-6,7-dihydro-4~{H}-pyrazolo[4,3-c]pyridin-1-yl]methyl]-1-bicyclo[2.2.2]octanyl]morpholine-3-carboxamide'>YHG</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=8pfi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8pfi OCA], [https://pdbe.org/8pfi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8pfi RCSB], [https://www.ebi.ac.uk/pdbsum/8pfi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8pfi 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 ==
Toll-like receptor (TLR) 7 and TLR8 are endosomal sensors of the innate immune system that are activated by GU-rich single stranded RNA (ssRNA). Multiple genetic and functional lines of evidence link chronic activation of TLR7/8 to the pathogenesis of systemic autoimmune diseases (sAID) such as Sjogren's syndrome (SjS) and systemic lupus erythematosus (SLE). This makes targeting TLR7/8-induced inflammation with small-molecule inhibitors an attractive approach for the treatment of patients suffering from systemic autoimmune diseases. Here, we describe how structure-based optimization of compound 2 resulted in the discovery of 34 (MHV370, (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide). Its in vivo activity allows for further profiling toward clinical trials in patients with autoimmune disorders, and a Phase 2 proof of concept study of MHV370 has been initiated, testing its safety and efficacy in patients with Sjogren's syndrome and mixed connective tissue disease.

Discovery of the TLR7/8 Antagonist MHV370 for Treatment of Systemic Autoimmune Diseases.,Alper P, Betschart C, Andre C, Boulay T, Cheng D, Deane J, Faller M, Feifel R, Glatthar R, Han D, Hemmig R, Jiang T, Knoepfel T, Maginnis J, Mutnick D, Pei W, Ruzzante G, Syka P, Zhang G, Zhang Y, Zink F, Zipfel G, Hawtin S, Junt T, Michellys PY ACS Med Chem Lett. 2023 Jul 31;14(8):1054-1062. doi: , 10.1021/acsmedchemlett.3c00136. eCollection 2023 Aug 10. PMID:37583811<ref>PMID:37583811</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8pfi" style="background-color:#fffaf0;"></div>

==See Also==
*[[Toll-like Receptor 3D structures|Toll-like Receptor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Faller M]]
[[Category: Zink F]]