1zeo
From Proteopedia
(New page: 200px<br /> <applet load="1zeo" size="450" color="white" frame="true" align="right" spinBox="true" caption="1zeo, resolution 2.50Å" /> '''Crystal Structure o...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:1zeo.gif|left|200px]]<br /> | + | [[Image:1zeo.gif|left|200px]]<br /><applet load="1zeo" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1zeo" size=" | + | |
caption="1zeo, resolution 2.50Å" /> | caption="1zeo, resolution 2.50Å" /> | ||
'''Crystal Structure of Human PPAR-gamma Ligand Binding Domain Complexed with an Alpha-Aryloxyphenylacetic Acid Agonist'''<br /> | '''Crystal Structure of Human PPAR-gamma Ligand Binding Domain Complexed with an Alpha-Aryloxyphenylacetic Acid Agonist'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The synthesis and structure-activity relationships of novel series of | + | The synthesis and structure-activity relationships of novel series of alpha-aryloxyphenylacetic acids as PPARalpha/gamma dual agonists are reported. The initial search for surrogates of the ester group in the screen lead led first to the optimization of a subseries with a ketone moiety. Further efforts to modify the ketone subseries led to the design and synthesis of two new subseries containing fused heterocyclic ring systems. All these analogues were characterized by their "super" PPARalpha agonist activity and weak or partial agonist activity on PPARgamma in PPAR-GAL4 transactivation assays despite their similar binding affinities for both receptors. The cocrystal structures of compounds 7 and rosiglitazone with PPARgamma-LBD were compared, and significant differences were found in their interactions with the receptor. Select analogues in each subseries were further evaluated for in vivo efficacy. They all showed excellent anti-hyperglycemic efficacy in a db/db mouse model and hypolipidemic activity in hamster and dog models without provoking the typical PPARgamma-associated side effects in the rat tolerability assay. |
==Disease== | ==Disease== | ||
| Line 11: | Line 10: | ||
==About this Structure== | ==About this Structure== | ||
| - | 1ZEO 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 C01 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1ZEO 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=C01:'>C01</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ZEO OCA]. |
==Reference== | ==Reference== | ||
| Line 17: | Line 16: | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Adams, A | + | [[Category: Adams, A D.]] |
| - | [[Category: Berger, J | + | [[Category: Berger, J P.]] |
| - | [[Category: Doebber, T | + | [[Category: Doebber, T W.]] |
| - | [[Category: Dropinski, J | + | [[Category: Dropinski, J F.]] |
[[Category: Elbrecht, A.]] | [[Category: Elbrecht, A.]] | ||
| - | [[Category: MacNaul, K | + | [[Category: MacNaul, K L.]] |
| - | [[Category: McKeever, B | + | [[Category: McKeever, B M.]] |
| - | [[Category: Shi, G | + | [[Category: Shi, G Q.]] |
[[Category: Zhou, G.]] | [[Category: Zhou, G.]] | ||
[[Category: C01]] | [[Category: C01]] | ||
| Line 33: | Line 32: | ||
[[Category: ppar-rxr heterodimer]] | [[Category: ppar-rxr heterodimer]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:14:48 2008'' |
Revision as of 14:14, 21 February 2008
|
Crystal Structure of Human PPAR-gamma Ligand Binding Domain Complexed with an Alpha-Aryloxyphenylacetic Acid Agonist
Contents |
Overview
The synthesis and structure-activity relationships of novel series of alpha-aryloxyphenylacetic acids as PPARalpha/gamma dual agonists are reported. The initial search for surrogates of the ester group in the screen lead led first to the optimization of a subseries with a ketone moiety. Further efforts to modify the ketone subseries led to the design and synthesis of two new subseries containing fused heterocyclic ring systems. All these analogues were characterized by their "super" PPARalpha agonist activity and weak or partial agonist activity on PPARgamma in PPAR-GAL4 transactivation assays despite their similar binding affinities for both receptors. The cocrystal structures of compounds 7 and rosiglitazone with PPARgamma-LBD were compared, and significant differences were found in their interactions with the receptor. Select analogues in each subseries were further evaluated for in vivo efficacy. They all showed excellent anti-hyperglycemic efficacy in a db/db mouse model and hypolipidemic activity in hamster and dog models without provoking the typical PPARgamma-associated side effects in the rat tolerability assay.
Disease
Known diseases associated with this structure: Abdominal body fat distribution, modifier of OMIM:[601487], Diabetes mellitus, insulin-resistant, with acanthosis nigricans and hypertension OMIM:[601487], Glioblastoma, susceptibility to OMIM:[601487], Insulin resistance, severe, digenic OMIM:[601487], Lipodystrophy, familial partial OMIM:[601487], Obesity, resistance to OMIM:[601487], Obesity, severe OMIM:[601487]
About this Structure
1ZEO is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
Reference
Design and synthesis of alpha-aryloxyphenylacetic acid derivatives: a novel class of PPARalpha/gamma dual agonists with potent antihyperglycemic and lipid modulating activity., Shi GQ, Dropinski JF, McKeever BM, Xu S, Becker JW, Berger JP, MacNaul KL, Elbrecht A, Zhou G, Doebber TW, Wang P, Chao YS, Forrest M, Heck JV, Moller DE, Jones AB, J Med Chem. 2005 Jun 30;48(13):4457-68. PMID:15974597
Page seeded by OCA on Thu Feb 21 16:14:48 2008
