3sz1

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{{STRUCTURE_3sz1| PDB=3sz1 | SCENE= }}
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==Human PPAR gamma ligand binding domain in complex with luteolin and myristic acid==
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===Human PPAR gamma ligand binding domain in complex with luteolin and myristic acid===
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<StructureSection load='3sz1' size='340' side='right' caption='[[3sz1]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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{{ABSTRACT_PUBMED_22391103}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3sz1]] 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=3SZ1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SZ1 FirstGlance]. <br>
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==Disease==
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=KNA:NONANOIC+ACID'>KNA</scene>, <scene name='pdbligand=LU2:2-(3,4-DIHYDROXYPHENYL)-5,7-DIHYDROXY-4H-CHROMEN-4-ONE'>LU2</scene>, <scene name='pdbligand=MYR:MYRISTIC+ACID'>MYR</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3om9|3om9]], [[1prg|1prg]], [[3pba|3pba]]</td></tr>
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<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>
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<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=3sz1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sz1 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3sz1 RCSB], [http://www.ebi.ac.uk/pdbsum/3sz1 PDBsum]</span></td></tr>
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</table>
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== 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.
[[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.
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== Function ==
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[[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Peroxisome proliferator-activated receptor gamma (PPARgamma) is a target for treatment of type II diabetes and other conditions. PPARgamma full agonists, like thiazolidinediones (TZDs), are effective insulin sensitizers and anti-inflammatories but their use is limited by adverse side effects. Luteolin is flavonoid with anti-inflammatory actions that binds PPARgamma but, unlike TZDs, does not promote adipocyte differentiation. However, previous reports variously suggested that luteolin is a PPARgamma agonist or an antagonist. We show that luteolin exhibits weak partial agonist/antagonist activity in transfections, inhibits several PPARgamma target genes in 3T3-L1 cells (LPL, ORL1 and CBPalpha) and PPARgamma-dependent adipogenesis but activates GLUT4 similarly to rosiglitazone implying gene-specific partial agonism. The crystal structure of the PPARgamma ligand binding domain (LBD) reveals that luteolin occupies buried ligand binding pocket (LBP) but binds an inactive PPARgamma LBD conformer and occupies a space near the beta-sheet region far from activation helix (H12) consistent with partial agonist/antagonist actions. A single myristic acid molecule simultaneously binds the LBP, suggesting that luteolin may cooperate with other ligands to bind PPARgamma, and molecular dynamics simulations show that luteolin and myristic acid cooperate to stabilize the Omega-loop between H2' and 3 and beta-sheet region. Interestingly, luteolin strongly suppresses hypertonicity-induced release of the pro-inflammatory IL-8 from human corneal epithelial cells (HCEC) and reverses reductions in transepithelial electrical resistance (TEER). This effect is PPARgamma dependent. We propose that activities of luteolin are related to its singular binding mode, that anti-inflammatory activity does not require H12 stabilization and that our structure can be useful in developing safe selective PPARgamma modulators.
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==Function==
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Mode of PPARgamma Activation by Luteolin.,Puhl AC, Bernardes A, Silveira RL, Yuan J, Campos JL, Saidemberg DM, Palma MS, Cvoro A, Ayers SD, Webb P, Reinach PS, Skaf MS, Polikarpov I Mol Pharmacol. 2012 Mar 5. PMID:22391103<ref>PMID:22391103</ref>
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[[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>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[3sz1]] 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=3SZ1 OCA].
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</div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:022391103</ref><references group="xtra"/><references/>
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*[[Peroxisome Proliferator-Activated Receptors|Peroxisome Proliferator-Activated Receptors]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Bernardes, A.]]
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[[Category: Bernardes, A]]
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[[Category: Polikarpov, I.]]
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[[Category: Polikarpov, I]]
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[[Category: Puhl, A C.]]
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[[Category: Puhl, A C]]
[[Category: Luteolin]]
[[Category: Luteolin]]
[[Category: Nuclear receptor]]
[[Category: Nuclear receptor]]
[[Category: Ppar gamma]]
[[Category: Ppar gamma]]
[[Category: Transcription]]
[[Category: Transcription]]

Revision as of 07:10, 21 December 2014

Human PPAR gamma ligand binding domain in complex with luteolin and myristic acid

3sz1, resolution 2.30Å

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