3r8a

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{{STRUCTURE_3r8a| PDB=3r8a | SCENE= }}
 
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===X-ray crystal structure of the nuclear hormone receptor PPAR-gamma in a complex with a compound with dual PPAR gamma agonism and Angiotensin II Type I receptor antagonism activity===
 
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{{ABSTRACT_PUBMED_21557540}}
 
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==Disease==
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==X-ray crystal structure of the nuclear hormone receptor PPAR-gamma in a complex with a compound with dual PPAR gamma agonism and Angiotensin II Type I receptor antagonism activity==
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[[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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<StructureSection load='3r8a' size='340' side='right' caption='[[3r8a]], [[Resolution|resolution]] 2.41&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3r8a]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3R8A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3R8A FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HIG:2-ETHYL-5,7-DIMETHYL-3-{(1S)-5-[2-(1H-TETRAZOL-5-YL)PHENYL]-2,3-DIHYDRO-1H-INDEN-1-YL}-3H-IMIDAZO[4,5-B]PYRIDINE'>HIG</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ia6|3ia6]], [[2q8s|2q8s]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NR1C3, PPARG ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3r8a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3r8a OCA], [http://pdbe.org/3r8a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3r8a RCSB], [http://www.ebi.ac.uk/pdbsum/3r8a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3r8a ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[[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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Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-gamma (PPARgamma) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPARgamma confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPARgamma activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobut yl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC(50) = 1.6 nM) with partial PPARgamma agonism (EC(50) = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.
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==Function==
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Discovery of a series of imidazo[4,5-b]pyridines with dual activity at angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-gamma.,Casimiro-Garcia A, Filzen GF, Flynn D, Bigge CF, Chen J, Davis JA, Dudley DA, Edmunds JJ, Esmaeil N, Geyer A, Heemstra RJ, Jalaie M, Ohren JF, Ostroski R, Ellis T, Schaum RP, Stoner C J Med Chem. 2011 Jun 23;54(12):4219-33. Epub 2011 May 26. PMID:21557540<ref>PMID:21557540</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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[[3r8a]] 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=3R8A OCA].
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</div>
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<div class="pdbe-citations 3r8a" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:021557540</ref><references group="xtra"/><references/>
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*[[Peroxisome Proliferator-Activated Receptors|Peroxisome Proliferator-Activated Receptors]]
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[[Category: Homo sapiens]]
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== References ==
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[[Category: Ohren, J F.]]
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Human]]
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[[Category: Ohren, J F]]
[[Category: Angiotensin ii type i receptor antagonist]]
[[Category: Angiotensin ii type i receptor antagonist]]
[[Category: Diabetes mellitus]]
[[Category: Diabetes mellitus]]

Revision as of 20:39, 5 August 2016

X-ray crystal structure of the nuclear hormone receptor PPAR-gamma in a complex with a compound with dual PPAR gamma agonism and Angiotensin II Type I receptor antagonism activity

3r8a, resolution 2.41Å

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