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1prg

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[[Image:1prg.gif|left|200px]]<br />
 
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<applet load="1prg" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1prg, resolution 2.20&Aring;" />
 
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'''LIGAND BINDING DOMAIN OF THE HUMAN PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA'''<br />
 
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==Overview==
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==LIGAND BINDING DOMAIN OF THE HUMAN PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA==
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The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a, ligand-dependent transcription factor that is important in adipocyte, differentiation and glucose homeostasis and which depends on interactions, with co-activators, including steroid receptor co-activating factor-1, (SRC-1). Here we present the X-ray crystal structure of the human, apo-PPAR-gamma ligand-binding domain (LBD), at 2.2 A resolution; this, structure reveals a large binding pocket, which may explain the diversity, of ligands for PPAR-gamma. We also describe the ternary complex containing, the PPAR-gamma LBD, the antidiabetic ligand rosiglitazone (BRL49653), and, 88 amino acids of human SRC-1 at 2.3 A resolution. Glutamate and lysine, residues that are highly conserved in LBDs of nuclear receptors form a, 'charge clamp' that contacts backbone atoms of the LXXLL helices of SRC-1., These results, together with the observation that two consecutive LXXLL, motifs of SRC-1 make identical contacts with both subunits of a PPAR-gamma, homodimer, suggest a general mechanism for the assembly of nuclear, receptors with co-activators.
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<StructureSection load='1prg' size='340' side='right'caption='[[1prg]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1prg]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PRG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1PRG FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2&#8491;</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1prg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1prg OCA], [https://pdbe.org/1prg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1prg RCSB], [https://www.ebi.ac.uk/pdbsum/1prg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1prg ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://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:[https://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:[https://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:[https://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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[https://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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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/pr/1prg_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1prg ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-dependent transcription factor that is important in adipocyte differentiation and glucose homeostasis and which depends on interactions with co-activators, including steroid receptor co-activating factor-1 (SRC-1). Here we present the X-ray crystal structure of the human apo-PPAR-gamma ligand-binding domain (LBD), at 2.2 A resolution; this structure reveals a large binding pocket, which may explain the diversity of ligands for PPAR-gamma. We also describe the ternary complex containing the PPAR-gamma LBD, the antidiabetic ligand rosiglitazone (BRL49653), and 88 amino acids of human SRC-1 at 2.3 A resolution. Glutamate and lysine residues that are highly conserved in LBDs of nuclear receptors form a 'charge clamp' that contacts backbone atoms of the LXXLL helices of SRC-1. These results, together with the observation that two consecutive LXXLL motifs of SRC-1 make identical contacts with both subunits of a PPAR-gamma homodimer, suggest a general mechanism for the assembly of nuclear receptors with co-activators.
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==About this Structure==
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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:9744270<ref>PMID:9744270</ref>
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1PRG is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Structure known Active Sites: LLL and LND. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1PRG OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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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://ispc.weizmann.ac.il//pmbin/getpm?pmid=9744270 9744270]
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</div>
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[[Category: Homo sapiens]]
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<div class="pdbe-citations 1prg" style="background-color:#fffaf0;"></div>
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[[Category: Single protein]]
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[[Category: Milburn, M.V.]]
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[[Category: Nolte, R.T.]]
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[[Category: Wisely, G.B.]]
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[[Category: apo]]
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[[Category: ligand-binding domain]]
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[[Category: nuclear receptor]]
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[[Category: orphan receptor]]
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[[Category: thiazolidinedione]]
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[[Category: transcription factor]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 14:56:41 2007''
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==See Also==
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*[[Peroxisome proliferator-activated receptor 3D structures|Peroxisome proliferator-activated receptor 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Milburn MV]]
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[[Category: Nolte RT]]
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[[Category: Wisely GB]]

Current revision

LIGAND BINDING DOMAIN OF THE HUMAN PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA

PDB ID 1prg

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