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==X-ray structure of human PPARalpha ligand binding domain-intrinsic fatty acid (E. coli origin)-CBP coactivator peptide co-crystals obtained by cross-seeding==
<StructureSection load='9iwl' size='340' side='right'caption='[[9iwl]], [[Resolution|resolution]] 2.09&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9iwl]] 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=9IWL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9IWL 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]] 2.09&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PLM:PALMITIC+ACID'>PLM</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=9iwl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9iwl OCA], [https://pdbe.org/9iwl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9iwl RCSB], [https://www.ebi.ac.uk/pdbsum/9iwl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9iwl ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PPARA_HUMAN PPARA_HUMAN] Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleylethanolamide, a naturally occurring lipid that regulates satiety (By similarity). Receptor for peroxisome proliferators such as hypolipidemic drugs and fatty acids. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the ACOX1 and P450 genes. Transactivation activity requires heterodimerization with RXRA and is antagonized by NR2C2.<ref>PMID:7684926</ref> <ref>PMID:7629123</ref> <ref>PMID:9556573</ref> <ref>PMID:10195690</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Peroxisome proliferator-activated receptors (PPARs), composed of the alpha/delta/gamma subtypes, are ligand-activated nuclear receptors/transcription factors that sense endogenous fatty acids or therapeutic drugs to regulate lipid/glucose metabolism and oxidative stress. PPAR forms a multiprotein complex with a retinoid X receptor and corepressor complex in an unliganded/inactive state, and ligand binding induces the replacement of the corepressor complex with the coactivator complex to initiate the transcription of various genes, including the metabolic and antioxidant ones. We investigated the processes by which the corepressor is replaced with the coactivator or in which two coactivators compete for the PPARalpha/delta/gamma-ligand-binding domains (LBDs) using single- and dual-emission fluorescence resonance energy transfer (FRET) assays. Single-FRET revealed that the respective PPARalpha/delta/gamma-selective agonists (pemafibrate, seladelpar, and pioglitazone) induced the dissociation of the two corepressor peptides, NCoR1 and NCoR2, from the PPARalpha/delta/gamma-LBDs and the recruitment of the two coactivator peptides, CBP and TRAP220. Meanwhile, dual-FRET demonstrated that these processes are simultaneous and that the four coactivator peptides, CBP, TRAP220, PGC1alpha, and SRC1, were competitively recruited to the PPARalpha/delta/gamma-LBDs with different preferences upon ligand activation. Furthermore, the five newly obtained cocrystal structures using X-ray diffraction, PPARalpha-LBDs-NCoR2/CBP/TRAP220/PGC1alpha and PPARgamma-LBD-NCoR2, were co-analyzed with those from our previous studies. This illustrates that these coactivators bound to the same PPARalpha-LBD loci via their consensus LXXLL motifs in the liganded state; that NCoR1/NCoR2 corepressors bound to the same loci via the IXXXL sequences within their consensus LXXXIXXXL motifs in the unliganded state; and that ligand activation induced AF-2 helix 12 formation that interfered with corepressor binding and created a binding space for the coactivator. These PPARalpha/gamma-related biochemical and physicochemical findings highlight the coregulator dynamics on limited PPARalpha/delta/gamma-LBDs loci.

Competitive Ligand-Induced Recruitment of Coactivators to Specific PPARalpha/delta/gamma Ligand-Binding Domains Revealed by Dual-Emission FRET and X-Ray Diffraction of Cocrystals.,Kamata S, Honda A, Yashiro S, Kaneko C, Komori Y, Shimamura A, Masuda R, Oyama T, Ishii I Antioxidants (Basel). 2025 Apr 20;14(4):494. doi: 10.3390/antiox14040494. PMID:40298866<ref>PMID:40298866</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9iwl" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Honda A]]
[[Category: Hosoda A]]
[[Category: Ishii I]]
[[Category: Kamata S]]
[[Category: Komori Y]]
[[Category: Oyama T]]
[[Category: Shimamura A]]
[[Category: Yashiro S]]