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==Design and biological evaluation of novel, balanced dual PPARa/g agonists== | |||
<StructureSection load='3fej' size='340' side='right'caption='[[3fej]], [[Resolution|resolution]] 2.01Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3fej]] 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=3FEJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3FEJ 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]] 2.01Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CTM:(2S)-3-(4-{[2-(4-CHLOROPHENYL)-1,3-THIAZOL-4-YL]METHOXY}-2-METHYLPHENYL)-2-ETHOXYPROPANOIC+ACID'>CTM</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=3fej FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fej OCA], [https://pdbe.org/3fej PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3fej RCSB], [https://www.ebi.ac.uk/pdbsum/3fej PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3fej 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/fe/3fej_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=3fej ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
An X-ray-guided design approach led to the identification of a novel, balanced class of alpha-ethoxy-phenylpropionic acid-derived dual PPARalpha/gamma agonists. The series shows a wide range of PPARalpha/gamma ratios within a rather narrow structural space. Advanced compounds possess favorable physicochemical and pharmacokinetic profiles and show a high efficacy in T2D and dyslipidemia animal models. | |||
Design and biological evaluation of novel, balanced dual PPARalpha/gamma agonists.,Grether U, Benardeau A, Benz J, Binggeli A, Blum D, Hilpert H, Kuhn B, Marki HP, Meyer M, Mohr P, Puntener K, Raab S, Ruf A, Schlatter D ChemMedChem. 2009 Jun;4(6):951-6. PMID:19326383<ref>PMID:19326383</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3fej" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Peroxisome proliferator-activated receptor 3D structures|Peroxisome proliferator-activated receptor 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Benz J]] | |||
[[Category: Binggeli A]] | |||
[[Category: Grether U]] | |||
[[Category: Gsell B]] | |||
[[Category: Hilpert H]] | |||
[[Category: Kuhn B]] | |||
[[Category: Maerki HP]] | |||
[[Category: Mohr P]] | |||
[[Category: Ruf A]] | |||
[[Category: Stihle M]] | |||