4e4k: Difference between revisions
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[[ | ==Crystal Structure of PPARgamma with the ligand JO21== | ||
<StructureSection load='4e4k' size='340' side='right' caption='[[4e4k]], [[Resolution|resolution]] 2.50Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4e4k]] is a 2 chain structure with 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=4E4K OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4E4K FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=RRG:(2S)-3-PHENYL-2-{[2-(PROPAN-2-YL)BIPHENYL-4-YL]OXY}PROPANOIC+ACID'>RRG</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3b3k|3b3k]], [[3k8s|3k8s]], [[4e4q|4e4q]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PPARG, NR1C3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4e4k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e4k OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4e4k RCSB], [http://www.ebi.ac.uk/pdbsum/4e4k PDBsum]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[http://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:[http://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:[http://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:[http://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 == | |||
[[http://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 == | |||
The preparation of a series of 2-(aryloxy)-3-phenylpropanoic acids, resulting from the introduction of different substituents into the biphenyl system of the previously reported peroxisome proliferator-activated receptor alpha/gamma (PPARalpha/gamma) dual agonist 1, allowed the identification of new ligands with higher potency on PPARalpha and fine-tuned moderate PPARgamma activity. For the most promising stereoisomer (S)-16, X-ray and calorimetric studies in PPARgamma revealed, at high ligand concentration, the presence of two molecules simultaneously bound to the receptor. On the basis of these results and docking experiments in both receptor subtypes, a molecular explanation was provided for its different behavior as a full and partial agonist of PPARalpha and PPARgamma, respectively. The effects of (S)-16 on mitochondrial acylcarnitine carrier and carnitine-palmitoyl-transferase 1 gene expression, two key components of the carnitine shuttle system, were also investigated, allowing the hypothesis of a more beneficial pharmacological profile of this compound compared to the less potent PPARalpha agonist fibrates currently used in therapy. | |||
New 2-(Aryloxy)-3-phenylpropanoic Acids as Peroxisome Proliferator-Activated Receptor alpha/gamma Dual Agonists Able To Upregulate Mitochondrial Carnitine Shuttle System Gene Expression.,Laghezza A, Pochetti G, Lavecchia A, Fracchiolla G, Faliti S, Piemontese L, Di Giovanni C, Iacobazzi V, Infantino V, Montanari R, Capelli D, Tortorella P, Loiodice F J Med Chem. 2013 Jan 10;56(1):60-72. doi: 10.1021/jm301018z. Epub 2012 Dec 18. PMID:23171045<ref>PMID:23171045</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | |||
*[[Peroxisome Proliferator-Activated Receptors|Peroxisome Proliferator-Activated Receptors]] | |||
== | == References == | ||
[[ | <references/> | ||
__TOC__ | |||
== | </StructureSection> | ||
< | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Carbonara, G | [[Category: Carbonara, G]] | ||
[[Category: Fracchiolla, G | [[Category: Fracchiolla, G]] | ||
[[Category: Laghezza, A | [[Category: Laghezza, A]] | ||
[[Category: Lavecchia, A | [[Category: Lavecchia, A]] | ||
[[Category: Loiodice, F | [[Category: Loiodice, F]] | ||
[[Category: Montanari, R | [[Category: Montanari, R]] | ||
[[Category: Novellino, E | [[Category: Novellino, E]] | ||
[[Category: Piemontese, L | [[Category: Piemontese, L]] | ||
[[Category: Pochetti, G | [[Category: Pochetti, G]] | ||
[[Category: Bundle of alpha-helices and a small four-stranded beta-sheet]] | [[Category: Bundle of alpha-helices and a small four-stranded beta-sheet]] | ||
[[Category: Transcription]] | [[Category: Transcription]] | ||
[[Category: Transcription factor]] | [[Category: Transcription factor]] | ||
Revision as of 19:35, 9 December 2014
Crystal Structure of PPARgamma with the ligand JO21Crystal Structure of PPARgamma with the ligand JO21
Structural highlights
Disease[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: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.[1] Defects in PPARG are the cause of familial partial lipodystrophy type 3 (FPLD3) [MIM: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.[2] [3] Genetic variations in PPARG can be associated with susceptibility to glioma type 1 (GLM1) [MIM: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[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.[4] [5] [6] Publication Abstract from PubMedThe preparation of a series of 2-(aryloxy)-3-phenylpropanoic acids, resulting from the introduction of different substituents into the biphenyl system of the previously reported peroxisome proliferator-activated receptor alpha/gamma (PPARalpha/gamma) dual agonist 1, allowed the identification of new ligands with higher potency on PPARalpha and fine-tuned moderate PPARgamma activity. For the most promising stereoisomer (S)-16, X-ray and calorimetric studies in PPARgamma revealed, at high ligand concentration, the presence of two molecules simultaneously bound to the receptor. On the basis of these results and docking experiments in both receptor subtypes, a molecular explanation was provided for its different behavior as a full and partial agonist of PPARalpha and PPARgamma, respectively. The effects of (S)-16 on mitochondrial acylcarnitine carrier and carnitine-palmitoyl-transferase 1 gene expression, two key components of the carnitine shuttle system, were also investigated, allowing the hypothesis of a more beneficial pharmacological profile of this compound compared to the less potent PPARalpha agonist fibrates currently used in therapy. New 2-(Aryloxy)-3-phenylpropanoic Acids as Peroxisome Proliferator-Activated Receptor alpha/gamma Dual Agonists Able To Upregulate Mitochondrial Carnitine Shuttle System Gene Expression.,Laghezza A, Pochetti G, Lavecchia A, Fracchiolla G, Faliti S, Piemontese L, Di Giovanni C, Iacobazzi V, Infantino V, Montanari R, Capelli D, Tortorella P, Loiodice F J Med Chem. 2013 Jan 10;56(1):60-72. doi: 10.1021/jm301018z. Epub 2012 Dec 18. PMID:23171045[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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