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==Human TLR8 bound to the potent agonist, GS-9688 (Selgantolimod)==
<StructureSection load='6wml' size='340' side='right'caption='[[6wml]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6WML OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6WML 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]] 2.5&#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=U57:(2R)-2-[(2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino]-2-methylhexan-1-ol'>U57</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=6wml FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wml OCA], [https://pdbe.org/6wml PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6wml RCSB], [https://www.ebi.ac.uk/pdbsum/6wml PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6wml ProSAT]</span></td></tr>
</table>
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== Publication Abstract from PubMed ==
Toll-like receptor 8 (TLR8) recognizes pathogen-derived single-stranded RNA fragments to trigger innate and adaptive immune responses. Chronic hepatitis B (CHB) is associated with a dysfunctional immune response, and therefore a selective TLR8 agonist may be an effective treatment option. Structure-based optimization of a dual TLR7/8 agonist led to the identification of the selective TLR8 clinical candidate (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (GS-9688, (R)-7). Potent TLR8 agonism (IL-12p40 EC50 = 220 nM) and &gt;100-fold TLR7 selectivity (IFN-alpha EC50 &gt; 50 muM) was observed in human peripheral blood mononuclear cells (PBMCs). The TLR8-ectodomain:(R)-7 complex confirmed TLR8 binding and a direct ligand interaction with TLR8 residue Asp545. Oral (R)-7 had good absorption and high first pass clearance in preclinical species. A reduction in viral markers was observed in HBV-infected primary human hepatocytes treated with media from PBMCs stimulated with (R)-7, supporting the clinical development of (R)-7 for the treatment of CHB.

Discovery of GS-9688 (Selgantolimod) as a Potent and Selective Oral Toll-Like Receptor 8 Agonist for the Treatment of Chronic Hepatitis B.,Mackman RL, Mish M, Chin G, Perry JK, Appleby T, Aktoudianakis V, Metobo S, Pyun P, Niu C, Daffis S, Yu H, Zheng J, Villasenor AG, Zablocki J, Chamberlain J, Jin H, Lee G, Suekawa-Pirrone K, Santos R, Delaney WE 4th, Fletcher SP J Med Chem. 2020 Sep 24;63(18):10188-10203. doi: 10.1021/acs.jmedchem.0c00100., Epub 2020 Jun 3. PMID:32407112<ref>PMID:32407112</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6wml" style="background-color:#fffaf0;"></div>

==See Also==
*[[Toll-like Receptor 3D structures|Toll-like Receptor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Appleby TC]]
[[Category: Mackman RL]]
[[Category: Mish M]]
[[Category: Perry JK]]
[[Category: Villasenor AG]]