2ath: Difference between revisions

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-[[Image:2ath.gif|left|200px]]<br /><applet load="2ath" size="350" color="white" frame="true" align="right" spinBox="true"
-caption="2ath, resolution 2.28&Aring;" />
-'''Crystal structure of the ligand binding domain of human PPAR-gamma im complex with an agonist'''<br />
-==Overview==
+==Crystal structure of the ligand binding domain of human PPAR-gamma im complex with an agonist==
-The synthesis and structure-activity relationship studies of novel indole derivatives as peroxisome proliferator-activated receptor (PPAR) agonists are reported. Indole, a drug-like scaffold, was studied as a core skeleton for the acidic head part of PPAR agonists. The structural features (acidic head, substitution on indole, and linker) were optimized first, by keeping benzisoxazole as the tail part, based on binding and functional activity at PPARgamma protein. The variations in the tail part, by introducing various heteroaromatic ring systems, were then studied. In vitro evaluation led to identification of a novel series of indole compounds with a benzisoxazole tail as potent PPAR agonists with the lead compound 14 (BPR1H036) displaying an excellent pharmacokinetic profile in BALB/c mice and an efficacious glucose lowering activity in KKA(y) mice. Structural biology studies of 14 showed that the indole ring contributes strong hydrophobic interactions with PPARgamma and could be an important moiety for the binding to the protein.
+<StructureSection load='2ath' size='340' side='right'caption='[[2ath]], [[Resolution|resolution]] 2.28&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2ath]] 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=2ATH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2ATH 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]] 2.28&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3EA:2-{5-[3-(7-PROPYL-3-TRIFLUOROMETHYLBENZO[D]ISOXAZOL-6-YLOXY)PROPOXY]INDOL-1-YL}ETHANOIC+ACID'>3EA</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=2ath FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ath OCA], [https://pdbe.org/2ath PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ath RCSB], [https://www.ebi.ac.uk/pdbsum/2ath PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ath ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[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.
+== 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>
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/at/2ath_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</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=2ath ConSurf].
+<div style="clear:both"></div>
-==Disease==
+==See Also==
-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]]
+*[[Peroxisome proliferator-activated receptor 3D structures|Peroxisome proliferator-activated receptor 3D structures]]
+== References ==
-==About this Structure==
+<references/>
-ATH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=3EA:'>3EA</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ATH OCA].
+__TOC__
+</StructureSection>
-==Reference==
-Novel indole-based peroxisome proliferator-activated receptor agonists: design, SAR, structural biology, and biological activities., Mahindroo N, Huang CF, Peng YH, Wang CC, Liao CC, Lien TW, Chittimalla SK, Huang WJ, Chai CH, Prakash E, Chen CP, Hsu TA, Peng CH, Lu IL, Lee LH, Chang YW, Chen WC, Chou YC, Chen CT, Goparaju CM, Chen YS, Lan SJ, Yu MC, Chen X, Chao YS, Wu SY, Hsieh HP, J Med Chem. 2005 Dec 29;48(26):8194-208. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16366601 16366601]
 [[Category: Homo sapiens]]
-[[Category: Single protein]]
+[[Category: Large Structures]]
-[[Category: Hsieh, H P.]]
+[[Category: Hsieh H-P]]
-[[Category: Huang, C F.]]
+[[Category: Huang C-F]]
-[[Category: Mahindroo, N.]]
+[[Category: Mahindroo N]]
-[[Category: Wu, S Y.]]
+[[Category: Wu S-Y]]
-[[Category: 3EA]]
-[[Category: ppar]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:30:50 2008''