1zeo

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[[Image:1zeo.gif|left|200px]]
 
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{{Structure
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==Crystal Structure of Human PPAR-gamma Ligand Binding Domain Complexed with an Alpha-Aryloxyphenylacetic Acid Agonist==
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|PDB= 1zeo |SIZE=350|CAPTION= <scene name='initialview01'>1zeo</scene>, resolution 2.50&Aring;
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<StructureSection load='1zeo' size='340' side='right'caption='[[1zeo]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
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|SITE=
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== Structural highlights ==
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|LIGAND= <scene name='pdbligand=C01:(2S)-(4-ISOPROPYLPHENYL)[(2-METHYL-3-OXO-5,7-DIPROPYL-2,3-DIHYDRO-1,2-BENZISOXAZOL-6-YL)OXY]ACETATE'>C01</scene>
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<table><tr><td colspan='2'>[[1zeo]] 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=1ZEO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1ZEO FirstGlance]. <br>
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|ACTIVITY=
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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]] 2.5&#8491;</td></tr>
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|GENE= PPARG, NR1C3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C01:(2S)-(4-ISOPROPYLPHENYL)[(2-METHYL-3-OXO-5,7-DIPROPYL-2,3-DIHYDRO-1,2-BENZISOXAZOL-6-YL)OXY]ACETATE'>C01</scene></td></tr>
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}}
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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=1zeo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1zeo OCA], [https://pdbe.org/1zeo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1zeo RCSB], [https://www.ebi.ac.uk/pdbsum/1zeo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1zeo ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/PPARG_HUMAN PPARG_HUMAN] Note=Defects in PPARG can lead to type 2 insulin-resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer. Defects in PPARG may be associated with susceptibility to obesity (OBESITY) [MIM:[https://omim.org/entry/601665 601665]. It is a condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.<ref>PMID:9753710</ref> Defects in PPARG are the cause of familial partial lipodystrophy type 3 (FPLD3) [MIM:[https://omim.org/entry/604367 604367]. Familial partial lipodystrophies (FPLD) are a heterogeneous group of genetic disorders characterized by marked loss of subcutaneous (sc) fat from the extremities. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia.<ref>PMID:12453919</ref> <ref>PMID:11788685</ref> Genetic variations in PPARG can be associated with susceptibility to glioma type 1 (GLM1) [MIM:[https://omim.org/entry/137800 137800]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Polymorphic PPARG alleles have been found to be significantly over-represented among a cohort of American patients with sporadic glioblastoma multiforme suggesting a possible contribution to disease susceptibility.
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== Function ==
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[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>
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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/ze/1zeo_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=1zeo ConSurf].
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<div style="clear:both"></div>
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'''Crystal Structure of Human PPAR-gamma Ligand Binding Domain Complexed with an Alpha-Aryloxyphenylacetic Acid Agonist'''
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==See Also==
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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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==Overview==
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<references/>
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The synthesis and structure-activity relationships of novel series of alpha-aryloxyphenylacetic acids as PPARalpha/gamma dual agonists are reported. The initial search for surrogates of the ester group in the screen lead led first to the optimization of a subseries with a ketone moiety. Further efforts to modify the ketone subseries led to the design and synthesis of two new subseries containing fused heterocyclic ring systems. All these analogues were characterized by their "super" PPARalpha agonist activity and weak or partial agonist activity on PPARgamma in PPAR-GAL4 transactivation assays despite their similar binding affinities for both receptors. The cocrystal structures of compounds 7 and rosiglitazone with PPARgamma-LBD were compared, and significant differences were found in their interactions with the receptor. Select analogues in each subseries were further evaluated for in vivo efficacy. They all showed excellent anti-hyperglycemic efficacy in a db/db mouse model and hypolipidemic activity in hamster and dog models without provoking the typical PPARgamma-associated side effects in the rat tolerability assay.
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__TOC__
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</StructureSection>
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==Disease==
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Known diseases associated with this structure: Abdominal body fat distribution, modifier of OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Diabetes mellitus, insulin-resistant, with acanthosis nigricans and hypertension OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Glioblastoma, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Insulin resistance, severe, digenic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Lipodystrophy, familial partial OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Obesity, resistance to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]], Obesity, severe OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601487 601487]]
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==About this Structure==
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1ZEO is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ZEO OCA].
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==Reference==
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Design and synthesis of alpha-aryloxyphenylacetic acid derivatives: a novel class of PPARalpha/gamma dual agonists with potent antihyperglycemic and lipid modulating activity., Shi GQ, Dropinski JF, McKeever BM, Xu S, Becker JW, Berger JP, MacNaul KL, Elbrecht A, Zhou G, Doebber TW, Wang P, Chao YS, Forrest M, Heck JV, Moller DE, Jones AB, J Med Chem. 2005 Jun 30;48(13):4457-68. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15974597 15974597]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Adams, A D.]]
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[[Category: Adams AD]]
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[[Category: Berger, J P.]]
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[[Category: Berger JP]]
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[[Category: Doebber, T W.]]
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[[Category: Doebber TW]]
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[[Category: Dropinski, J F.]]
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[[Category: Dropinski JF]]
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[[Category: Elbrecht, A.]]
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[[Category: Elbrecht A]]
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[[Category: MacNaul, K L.]]
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[[Category: MacNaul KL]]
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[[Category: McKeever, B M.]]
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[[Category: McKeever BM]]
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[[Category: Shi, G Q.]]
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[[Category: Shi GQ]]
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[[Category: Zhou, G.]]
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[[Category: Zhou G]]
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[[Category: C01]]
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[[Category: alpha helix sandwich]]
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[[Category: lbd]]
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[[Category: ligand binding domain]]
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[[Category: nuclear receptor]]
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[[Category: ppar-rxr heterodimer]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 15:34:37 2008''
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Current revision

Crystal Structure of Human PPAR-gamma Ligand Binding Domain Complexed with an Alpha-Aryloxyphenylacetic Acid Agonist

PDB ID 1zeo

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