4fgy: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4fgy]] 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=4FGY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4FGY FirstGlance]. <br>
<table><tr><td colspan='2'>[[4fgy]] 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=4FGY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4FGY FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0W3:(4R,6S,8S,12R,14R,16Z,18R,19R,20S,21S)-19,21-DIHYDROXY-22-{(2S,2R,5S,5S)-5-[(1R)-1-HYDROXYETHYL]-2,5-DIMETHYLOCTAHYDRO-2,2-BIFURAN-5-YL}-4,6,8,12,14,18,20-HEPTAMETHYL-9,11-DIOXODOCOS-16-ENOIC+ACID'>0W3</scene></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]] 2.84&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0W3:(4R,6S,8S,12R,14R,16Z,18R,19R,20S,21S)-19,21-DIHYDROXY-22-{(2S,2R,5S,5S)-5-[(1R)-1-HYDROXYETHYL]-2,5-DIMETHYLOCTAHYDRO-2,2-BIFURAN-5-YL}-4,6,8,12,14,18,20-HEPTAMETHYL-9,11-DIOXODOCOS-16-ENOIC+ACID'>0W3</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=4fgy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fgy OCA], [https://pdbe.org/4fgy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4fgy RCSB], [https://www.ebi.ac.uk/pdbsum/4fgy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4fgy ProSAT]</span></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=4fgy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fgy OCA], [https://pdbe.org/4fgy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4fgy RCSB], [https://www.ebi.ac.uk/pdbsum/4fgy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4fgy ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
== Function ==
[https://www.uniprot.org/uniprot/PPARG_HUMAN PPARG_HUMAN] Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses.<ref>PMID:9065481</ref> <ref>PMID:16150867</ref> <ref>PMID:20829347</ref>  
[https://www.uniprot.org/uniprot/PPARG_HUMAN PPARG_HUMAN] Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses.<ref>PMID:9065481</ref> <ref>PMID:16150867</ref> <ref>PMID:20829347</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
AIMS/HYPOTHESIS: Existing thiazolidinedione (TZD) drugs for diabetes have severe side effects. The aim of this study is to develop alternative peroxisome proliferator-activated receptor gamma (PPARgamma) ligands that retain the benefits in improving insulin resistance but with reduced side effects. METHODS: We used AlphaScreen assay to screen for new PPARgamma ligands from compound libraries. In vitro biochemical binding affinity assay and in vivo cell-based reporter assay were used to validate ionomycin as a partial ligand of PPARgamma. A mouse model of diabetes was used to assess the effects of ionomycin in improving insulin sensitivity. Crystal structure of PPARgamma complexed with ionomycin revealed the unique binding mode of ionomycin, which elucidated the molecular mechanisms allowing the discrimination of ionomycin from TZDs. RESULTS: We found that the antibiotic ionomycin is a novel modulating ligand for PPARgamma. Both the transactivation and binding activity of PPARgamma by ionomycin can be blocked by PPARgamma specific antagonist GW9662. Ionomycin interacts with the PPARgamma ligand-binding domain in a unique binding mode with properties and epitopes distinct from those of TZD drugs. Ionomycin treatment effectively improved hyperglycaemia and insulin resistance, but had reduced side effects compared with TZDs in the mouse model of diabetes. In addition, ionomycin effectively blocked the phosphorylation of PPARgamma at Ser273 by cyclin-dependent kinase 5 both in vitro and in vivo. CONCLUSIONS/INTERPRETATION: Our studies suggest that ionomycin may represent a unique template for designing novel PPARgamma ligands with advantages over current TZD drugs.
Identification of the antibiotic ionomycin as an unexpected peroxisome proliferator-activated receptor gamma (PPARgamma) ligand with a unique binding mode and effective glucose-lowering activity in a mouse model of diabetes.,Zheng W, Feng X, Qiu L, Pan Z, Wang R, Lin S, Hou D, Jin L, Li Y Diabetologia. 2013 Feb;56(2):401-11. doi: 10.1007/s00125-012-2777-9. Epub 2012, Nov 23. PMID:23178929<ref>PMID:23178929</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4fgy" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==

Latest revision as of 11:16, 1 March 2024

Identification of a unique PPAR ligand with an unexpected binding mode and antibetic activity

4fgy, resolution 2.84Å

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