2i4j

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{{STRUCTURE_2i4j| PDB=2i4j | SCENE= }}
{{STRUCTURE_2i4j| PDB=2i4j | SCENE= }}
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'''Crystal structure of the complex between PPARgamma and the agonist LT160 (ureidofibrate derivative)'''
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===Crystal structure of the complex between PPARgamma and the agonist LT160 (ureidofibrate derivative)===
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==Overview==
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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 targets 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. Most importantly, we report the x-ray crystal structures of the PPARgamma ligand binding domain complexed with the R- and the S-enantiomer, respectively. 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 Leu(465), Leu(469), and Ile(472) in the activation by (R)-1 and underscores the key role of Gln(286) in the PPARgamma activity.
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(as it appears on PubMed at http://www.pubmed.gov), where 17403688 is the PubMed ID number.
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{{ABSTRACT_PUBMED_17403688}}
==About this Structure==
==About this Structure==
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==Reference==
==Reference==
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 Jun 8;282(23):17314-24. Epub 2007 Apr 2. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17403688 17403688]
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 Jun 8;282(23):17314-24. Epub 2007 Apr 2. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17403688 17403688]
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Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma., Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, Rosenfeld MG, Willson TM, Glass CK, Milburn MV, Nature. 1998 Sep 10;395(6698):137-43. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/9744270 9744270]
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A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte differentiation., Oberfield JL, Collins JL, Holmes CP, Goreham DM, Cooper JP, Cobb JE, Lenhard JM, Hull-Ryde EA, Mohr CP, Blanchard SG, Parks DJ, Moore LB, Lehmann JM, Plunket K, Miller AB, Milburn MV, Kliewer SA, Willson TM, Proc Natl Acad Sci U S A. 1999 May 25;96(11):6102-6. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/10339548 10339548]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Single protein]]
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[[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]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 07:03:30 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 11:14:52 2008''

Revision as of 08:14, 28 July 2008

Image:2i4j.png

Template:STRUCTURE 2i4j

Crystal structure of the complex between PPARgamma and the agonist LT160 (ureidofibrate derivative)

Template:ABSTRACT PUBMED 17403688

About this Structure

2I4J is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

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 Jun 8;282(23):17314-24. Epub 2007 Apr 2. PMID:17403688

Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma., Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, Rosenfeld MG, Willson TM, Glass CK, Milburn MV, Nature. 1998 Sep 10;395(6698):137-43. PMID:9744270

A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte differentiation., Oberfield JL, Collins JL, Holmes CP, Goreham DM, Cooper JP, Cobb JE, Lenhard JM, Hull-Ryde EA, Mohr CP, Blanchard SG, Parks DJ, Moore LB, Lehmann JM, Plunket K, Miller AB, Milburn MV, Kliewer SA, Willson TM, Proc Natl Acad Sci U S A. 1999 May 25;96(11):6102-6. PMID:10339548

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