2i4j: Difference between revisions
New page: left|200px<br /> <applet load="2i4j" size="450" color="white" frame="true" align="right" spinBox="true" caption="2i4j, resolution 2.100Å" /> '''Crystal structure ... |
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[[Image:2i4j.gif|left|200px]]<br /> | [[Image:2i4j.gif|left|200px]]<br /><applet load="2i4j" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="2i4j, resolution 2.100Å" /> | caption="2i4j, resolution 2.100Å" /> | ||
'''Crystal structure of the complex between PPARgamma and the agonist LT160 (ureidofibrate derivative)'''<br /> | '''Crystal structure of the complex between PPARgamma and the agonist LT160 (ureidofibrate derivative)'''<br /> | ||
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==Overview== | ==Overview== | ||
The peroxisome proliferator-activated receptors (PPARs) are, transcriptional regulators of glucose and lipid metabolism. They are, activated by natural ligands, such as fatty acids, and are also target of, synthetic antidiabetic and hypolipidemic drugs. By using cell-based, reporter assays, we studied the transactivation activity of two, enantiomeric ureidofibrate-like derivatives. In particular, we show that, the R-enantiomer, (R)-1, is a full agonist of PPARgamma, whereas the, S-enantiomer, (S)-1, is a less potent partial agonist. These two molecules, affect specifically the transcriptional activity of PPARalpha and gamma, subtypes, whereas the activity of other members of the nuclear receptor, gene superfamily is not altered. Most importantly, we report the X-ray, crystal structures of the PPARgamma ligand binding domain respectively, complexed with the R- and the S-enantiomer. The analysis of the two, crystal structures shows that the different degree of stabilization of the, helix 12 induced by the ligand determines its behavior as full or partial, agonist. Another crystal structure of the PPARgamma/(S)-1 complex, only, differing in the soaking time of the ligand, is also presented. The, comparison of the two structures of the complexes with the partial agonist, reveals significant differences and is suggestive of the possible, coexistence in solution of transcriptionally active and inactive forms of, helix 12 in the presence of a partial agonist. Mutation analysis confirms, the importance of L465, L469 and I472 in the activation by (R)-1 and, underscores the key role of Q286 in the PPARgamma activity. | The peroxisome proliferator-activated receptors (PPARs) are, transcriptional regulators of glucose and lipid metabolism. They are, activated by natural ligands, such as fatty acids, and are also target of, synthetic antidiabetic and hypolipidemic drugs. By using cell-based, reporter assays, we studied the transactivation activity of two, enantiomeric ureidofibrate-like derivatives. In particular, we show that, the R-enantiomer, (R)-1, is a full agonist of PPARgamma, whereas the, S-enantiomer, (S)-1, is a less potent partial agonist. These two molecules, affect specifically the transcriptional activity of PPARalpha and gamma, subtypes, whereas the activity of other members of the nuclear receptor, gene superfamily is not altered. Most importantly, we report the X-ray, crystal structures of the PPARgamma ligand binding domain respectively, complexed with the R- and the S-enantiomer. The analysis of the two, crystal structures shows that the different degree of stabilization of the, helix 12 induced by the ligand determines its behavior as full or partial, agonist. Another crystal structure of the PPARgamma/(S)-1 complex, only, differing in the soaking time of the ligand, is also presented. The, comparison of the two structures of the complexes with the partial agonist, reveals significant differences and is suggestive of the possible, coexistence in solution of transcriptionally active and inactive forms of, helix 12 in the presence of a partial agonist. Mutation analysis confirms, the importance of L465, L469 and I472 in the activation by (R)-1 and, underscores the key role of Q286 in the PPARgamma activity. | ||
==About this Structure== | ==About this Structure== | ||
2I4J 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 DRJ as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | 2I4J 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=DRJ:'>DRJ</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2I4J OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: bundle of alpha-helices and a small four-stranded beta-sheet]] | [[Category: bundle of alpha-helices and a small four-stranded beta-sheet]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 14:42:49 2008'' | ||
Revision as of 15:42, 23 January 2008
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Crystal structure of the complex between PPARgamma and the agonist LT160 (ureidofibrate derivative)
OverviewOverview
The peroxisome proliferator-activated receptors (PPARs) are, transcriptional regulators of glucose and lipid metabolism. They are, activated by natural ligands, such as fatty acids, and are also target of, synthetic antidiabetic and hypolipidemic drugs. By using cell-based, reporter assays, we studied the transactivation activity of two, enantiomeric ureidofibrate-like derivatives. In particular, we show that, the R-enantiomer, (R)-1, is a full agonist of PPARgamma, whereas the, S-enantiomer, (S)-1, is a less potent partial agonist. These two molecules, affect specifically the transcriptional activity of PPARalpha and gamma, subtypes, whereas the activity of other members of the nuclear receptor, gene superfamily is not altered. Most importantly, we report the X-ray, crystal structures of the PPARgamma ligand binding domain respectively, complexed with the R- and the S-enantiomer. The analysis of the two, crystal structures shows that the different degree of stabilization of the, helix 12 induced by the ligand determines its behavior as full or partial, agonist. Another crystal structure of the PPARgamma/(S)-1 complex, only, differing in the soaking time of the ligand, is also presented. The, comparison of the two structures of the complexes with the partial agonist, reveals significant differences and is suggestive of the possible, coexistence in solution of transcriptionally active and inactive forms of, helix 12 in the presence of a partial agonist. Mutation analysis confirms, the importance of L465, L469 and I472 in the activation by (R)-1 and, underscores the key role of Q286 in the PPARgamma activity.
About this StructureAbout this Structure
2I4J is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Insights into the mechanism of partial agonism: crystal structures of the peroxisome proliferator-activated receptor gamma ligand-binding domain in the complex with two enantiomeric ligands., Pochetti G, Godio C, Mitro N, Caruso D, Galmozzi A, Scurati S, Loiodice F, Fracchiolla G, Tortorella P, Laghezza A, Lavecchia A, Novellino E, Mazza F, Crestani M, J Biol Chem. 2007 Apr 2;. PMID:17403688
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