2p54: Difference between revisions
New page: left|200px<br /> <applet load="2p54" size="450" color="white" frame="true" align="right" spinBox="true" caption="2p54, resolution 1.79Å" /> '''a crystal structure... |
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[[Image:2p54.gif|left|200px]]<br /> | [[Image:2p54.gif|left|200px]]<br /><applet load="2p54" size="350" color="white" frame="true" align="right" spinBox="true" | ||
<applet load="2p54" size=" | |||
caption="2p54, resolution 1.79Å" /> | caption="2p54, resolution 1.79Å" /> | ||
'''a crystal structure of PPAR alpha bound with SRC1 peptide and GW735'''<br /> | '''a crystal structure of PPAR alpha bound with SRC1 peptide and GW735'''<br /> | ||
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==Overview== | ==Overview== | ||
The peroxisome proliferator activated receptors PPARalpha, PPARgamma, and, PPARdelta are ligand-activated transcription factors that play a key role, in lipid homeostasis. The fibrates raise circulating levels of, high-density lipoprotein cholesterol and lower levels of triglycerides in, part through their activity as PPARalpha agonists; however, the low, potency and restricted selectivity of the fibrates may limit their, efficacy, and it would be desirable to develop more potent and selective, PPARalpha agonists. Modification of the selective PPARdelta agonist 1, (GW501516) so as to incorporate the 2-aryl-2-methylpropionic acid group of, the fibrates led to a marked shift in potency and selectivity toward, PPARalpha agonism. Optimization of the series gave 25a, which shows EC50 =, 4 nM on PPARalpha and at least 500-fold selectivity versus PPARdelta and, PPARgamma. Compound 25a (GW590735) has been progressed to clinical trials, for the treatment of diseases of lipid imbalance. | The peroxisome proliferator activated receptors PPARalpha, PPARgamma, and, PPARdelta are ligand-activated transcription factors that play a key role, in lipid homeostasis. The fibrates raise circulating levels of, high-density lipoprotein cholesterol and lower levels of triglycerides in, part through their activity as PPARalpha agonists; however, the low, potency and restricted selectivity of the fibrates may limit their, efficacy, and it would be desirable to develop more potent and selective, PPARalpha agonists. Modification of the selective PPARdelta agonist 1, (GW501516) so as to incorporate the 2-aryl-2-methylpropionic acid group of, the fibrates led to a marked shift in potency and selectivity toward, PPARalpha agonism. Optimization of the series gave 25a, which shows EC50 =, 4 nM on PPARalpha and at least 500-fold selectivity versus PPARdelta and, PPARgamma. Compound 25a (GW590735) has been progressed to clinical trials, for the treatment of diseases of lipid imbalance. | ||
==About this Structure== | ==About this Structure== | ||
2P54 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with 735 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Histone_acetyltransferase Histone acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.48 2.3.1.48] Full crystallographic information is available from [http:// | 2P54 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=735:'>735</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Histone_acetyltransferase Histone acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.48 2.3.1.48] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2P54 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: ppar alpha gw735 src1 agonist hdlc]] | [[Category: ppar alpha gw735 src1 agonist hdlc]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 15:36:26 2008'' | ||
Revision as of 16:36, 23 January 2008
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a crystal structure of PPAR alpha bound with SRC1 peptide and GW735
OverviewOverview
The peroxisome proliferator activated receptors PPARalpha, PPARgamma, and, PPARdelta are ligand-activated transcription factors that play a key role, in lipid homeostasis. The fibrates raise circulating levels of, high-density lipoprotein cholesterol and lower levels of triglycerides in, part through their activity as PPARalpha agonists; however, the low, potency and restricted selectivity of the fibrates may limit their, efficacy, and it would be desirable to develop more potent and selective, PPARalpha agonists. Modification of the selective PPARdelta agonist 1, (GW501516) so as to incorporate the 2-aryl-2-methylpropionic acid group of, the fibrates led to a marked shift in potency and selectivity toward, PPARalpha agonism. Optimization of the series gave 25a, which shows EC50 =, 4 nM on PPARalpha and at least 500-fold selectivity versus PPARdelta and, PPARgamma. Compound 25a (GW590735) has been progressed to clinical trials, for the treatment of diseases of lipid imbalance.
About this StructureAbout this Structure
2P54 is a Protein complex structure of sequences from Homo sapiens with as ligand. Active as Histone acetyltransferase, with EC number 2.3.1.48 Full crystallographic information is available from OCA.
ReferenceReference
Substituted 2-[(4-aminomethyl)phenoxy]-2-methylpropionic acid PPARalpha agonists. 1. Discovery of a novel series of potent HDLc raising agents., Sierra ML, Beneton V, Boullay AB, Boyer T, Brewster AG, Donche F, Forest MC, Fouchet MH, Gellibert FJ, Grillot DA, Lambert MH, Laroze A, Le Grumelec C, Linget JM, Montana VG, Nguyen VL, Nicodeme E, Patel V, Penfornis A, Pineau O, Pohin D, Potvain F, Poulain G, Ruault CB, Saunders M, Toum J, Xu HE, Xu RX, Pianetti PM, J Med Chem. 2007 Feb 22;50(4):685-95. Epub 2007 Jan 23. PMID:17243659
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