View source for 8hf8


==Human PPAR delta ligand binding domain in complex with a synthetic agonist V1==
<StructureSection load='8hf8' size='340' side='right'caption='[[8hf8]], [[Resolution|resolution]] 2.11&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8hf8]] 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=8HF8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8HF8 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]] 2.11&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=LOO:2-[4-[[2,5-bis(oxidanylidene)-3-[4-(trifluoromethyl)phenyl]imidazolidin-1-yl]methyl]-2,6-dimethyl-phenoxy]-2-methyl-propanoic+acid'>LOO</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=8hf8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8hf8 OCA], [https://pdbe.org/8hf8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8hf8 RCSB], [https://www.ebi.ac.uk/pdbsum/8hf8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8hf8 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PPARD_HUMAN PPARD_HUMAN] Ligand-activated transcription factor. Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Has a preference for poly-unsaturated fatty acids, such as gamma-linoleic acid and eicosapentanoic acid. Once activated by a ligand, the receptor binds to promoter elements of target genes. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the acyl-CoA oxidase gene. Decreases expression of NPC1L1 once activated by a ligand.<ref>PMID:1333051</ref> <ref>PMID:15604518</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Peroxisome proliferator-activator receptors alpha/delta (PPARalpha/delta) are considered as potential drug targets for cholestatic liver diseases (CLD) via ameliorating hepatic cholestasis, inflammation, and fibrosis. In this work, we developed a series of hydantoin derivatives as potent PPARalpha/delta dual agonists. Representative compound V1 exhibited PPARalpha/delta dual agonistic activity at the subnanomolar level (PPARalpha EC(50) = 0.7 nM; PPARdelta EC(50) = 0.4 nM) and showed excellent selectivity over other related nuclear receptors. The crystal structure revealed the binding mode of V1 and PPARdelta at 2.1 A resolution. Importantly, V1 demonstrated excellent pharmacokinetic (PK) properties and a good safety profile. Notably, V1 showed potent anti-CLD and antifibrotic effects in preclinical models at very low doses (0.03 and 0.1 mg/kg). Collectively, this work provides a promising drug candidate for treating CLD and other hepatic fibrosis diseases.

Discovery of the First Subnanomolar PPARalpha/delta Dual Agonist for the Treatment of Cholestatic Liver Diseases.,Feng Z, Xiang J, Sun G, Liu H, Wang Y, Liu X, Feng J, Xu Q, Wen X, Yuan H, Sun H, Dai L J Med Chem. 2023 Jun 8;66(11):7331-7354. doi: 10.1021/acs.jmedchem.2c02123. Epub , 2023 May 27. PMID:37243609<ref>PMID:37243609</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8hf8" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Dai L]]
[[Category: Feng ZQ]]
[[Category: Sun HB]]
[[Category: Yuan HL]]