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2p54

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(New page: 200px<br /> <applet load="2p54" size="450" color="white" frame="true" align="right" spinBox="true" caption="2p54, resolution 1.79&Aring;" /> '''a crystal structure...)
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[[Image:2p54.gif|left|200px]]<br />
 
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<applet load="2p54" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="2p54, resolution 1.79&Aring;" />
 
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'''a crystal structure of PPAR alpha bound with SRC1 peptide and GW735'''<br />
 
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==Overview==
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==a crystal structure of PPAR alpha bound with SRC1 peptide and GW735==
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The peroxisome proliferator activated receptors PPARalpha, PPARgamma, and, PPARdelta are ligand-activated transcription factors that play a key role, in lipid homeostasis. The fibrates raise circulating levels of, high-density lipoprotein cholesterol and lower levels of triglycerides in, part through their activity as PPARalpha agonists; however, the low, potency and restricted selectivity of the fibrates may limit their, efficacy, and it would be desirable to develop more potent and selective, PPARalpha agonists. Modification of the selective PPARdelta agonist 1, (GW501516) so as to incorporate the 2-aryl-2-methylpropionic acid group of, the fibrates led to a marked shift in potency and selectivity toward, PPARalpha agonism. Optimization of the series gave 25a, which shows EC50 =, 4 nM on PPARalpha and at least 500-fold selectivity versus PPARdelta and, PPARgamma. Compound 25a (GW590735) has been progressed to clinical trials, for the treatment of diseases of lipid imbalance.
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<StructureSection load='2p54' size='340' side='right'caption='[[2p54]], [[Resolution|resolution]] 1.79&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2p54]] 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=2P54 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2P54 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.79&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=735:2-METHYL-2-(4-{[({4-METHYL-2-[4-(TRIFLUOROMETHYL)PHENYL]-1,3-THIAZOL-5-YL}CARBONYL)AMINO]METHYL}PHENOXY)PROPANOIC+ACID'>735</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2p54 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2p54 OCA], [https://pdbe.org/2p54 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2p54 RCSB], [https://www.ebi.ac.uk/pdbsum/2p54 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2p54 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/p5/2p54_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2p54 ConSurf].
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<div style="clear:both"></div>
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==Disease==
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==See Also==
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Known diseases associated with this structure: Hyperapobetalipoproteinemia, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=170998 170998]]
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*[[Peroxisome proliferator-activated receptor 3D structures|Peroxisome proliferator-activated receptor 3D structures]]
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== References ==
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==About this Structure==
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<references/>
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2P54 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with 735 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Histone_acetyltransferase Histone acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.48 2.3.1.48] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2P54 OCA].
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__TOC__
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</StructureSection>
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==Reference==
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Substituted 2-[(4-aminomethyl)phenoxy]-2-methylpropionic acid PPARalpha agonists. 1. Discovery of a novel series of potent HDLc raising agents., Sierra ML, Beneton V, Boullay AB, Boyer T, Brewster AG, Donche F, Forest MC, Fouchet MH, Gellibert FJ, Grillot DA, Lambert MH, Laroze A, Le Grumelec C, Linget JM, Montana VG, Nguyen VL, Nicodeme E, Patel V, Penfornis A, Pineau O, Pohin D, Potvain F, Poulain G, Ruault CB, Saunders M, Toum J, Xu HE, Xu RX, Pianetti PM, J Med Chem. 2007 Feb 22;50(4):685-95. Epub 2007 Jan 23. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17243659 17243659]
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[[Category: Histone acetyltransferase]]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Protein complex]]
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[[Category: Large Structures]]
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[[Category: Lambert, M.H.]]
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[[Category: Lambert MH]]
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[[Category: Montana, V.G.]]
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[[Category: Montana VG]]
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[[Category: Pianetti, P.M.]]
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[[Category: Pianetti PM]]
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[[Category: Sierra, M.L.]]
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[[Category: Sierra ML]]
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[[Category: Xu, H.E.]]
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[[Category: Xu HE]]
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[[Category: Xu, R.X.]]
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[[Category: Xu RX]]
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[[Category: 735]]
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[[Category: ppar alpha gw735 src1 agonist hdlc]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 23:20:41 2007''
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Current revision

a crystal structure of PPAR alpha bound with SRC1 peptide and GW735

PDB ID 2p54

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