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| | ==Crystal structure of PPAR gamma ligand binding domain in complex with a novel partial agonist GQ-16== | | ==Crystal structure of PPAR gamma ligand binding domain in complex with a novel partial agonist GQ-16== |
| - | <StructureSection load='3t03' size='340' side='right' caption='[[3t03]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='3t03' size='340' side='right'caption='[[3t03]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3t03]] is a 4 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=3T03 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3T03 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3t03]] is a 4 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=3T03 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3T03 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3T0:(5Z)-5-(5-BROMO-2-METHOXYBENZYLIDENE)-3-(4-METHYLBENZYL)-1,3-THIAZOLIDINE-2,4-DIONE'>3T0</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3T0:(5Z)-5-(5-BROMO-2-METHOXYBENZYLIDENE)-3-(4-METHYLBENZYL)-1,3-THIAZOLIDINE-2,4-DIONE'>3T0</scene></td></tr> |
| - | <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=3t03 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t03 OCA], [http://pdbe.org/3t03 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3t03 RCSB], [http://www.ebi.ac.uk/pdbsum/3t03 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3t03 ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3t03 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t03 OCA], [https://pdbe.org/3t03 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3t03 RCSB], [https://www.ebi.ac.uk/pdbsum/3t03 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3t03 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[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. [[http://www.uniprot.org/uniprot/NCOA1_HUMAN NCOA1_HUMAN]] Note=A chromosomal aberration involving NCOA1 is a cause of rhabdomyosarcoma. Translocation t(2;2)(q35;p23) with PAX3 generates the NCOA1-PAX3 oncogene consisting of the N-terminus part of PAX3 and the C-terminus part of NCOA1. The fusion protein acts as a transcriptional activator. Rhabdomyosarcoma is the most common soft tissue carcinoma in childhood, representing 5-8% of all malignancies in children. | + | [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. |
| | == Function == | | == Function == |
| - | [[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> [[http://www.uniprot.org/uniprot/NCOA1_HUMAN NCOA1_HUMAN]] Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs). Also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors. Displays histone acetyltransferase activity toward H3 and H4; the relevance of such activity remains however unclear. Plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. Required with NCOA2 to control energy balance between white and brown adipose tissues. Required for mediating steroid hormone response. Isoform 2 has a higher thyroid hormone-dependent transactivation activity than isoform 1 and isoform 3.<ref>PMID:9427757</ref> <ref>PMID:7481822</ref> <ref>PMID:9223431</ref> <ref>PMID:9296499</ref> <ref>PMID:9223281</ref> <ref>PMID:10449719</ref> <ref>PMID:12954634</ref> | + | [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> |
| - | <div style="background-color:#fffaf0;">
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| - | == Publication Abstract from PubMed ==
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| - | The recent discovery that PPARg targeted anti-diabetic drugs function by inhibiting Cdk5 mediated phosphorylation of the receptor has provided a new viewpoint to evaluate and perhaps develop improved insulin sensitizing agents. Herein we report the development of novel thiazolidinediones that retain similar anti-diabetic efficacy as rosiglitazone, yet do not elicit weight gain or edema, common side effects associated with PPARg activation. Further characterization of one these compounds show GQ-16 to be an effective inhibitor of Cdk5 phosphorylation of PPARg. The structure of GQ-16 bound to PPARg demonstrates that the compound utilizes a binding mode distinct from other reported PPARg ligands, although it does share structural features with other partial agonists such as MRL-24 and PA-082 that have similarly been reported to dissociate insulin sensitization from weight gain. Hydrogen-deuterium exchange studies reveal that GQ-16 strongly stabilizes the beta-sheet region of the receptor, presumably explaining the compounds efficacy in inhibiting Cdk5 phosphorylation of S273. Molecular dynamics simulations affirm the partial agonist activity of GQ-16 indicating that the compound prevents helix 12 from docking efficiently in the active conformation. Our results here suggest that the emerging model, whereby "ideal" PPARg-based therapeutics stabilize the beta-sheet/S273 region and inhibit Cdk5 phosphorylation while minimally invoking adipogenesis and classical agonism, is indeed a valid framework to develop improved PPARg modulators that retain anti-diabetic actions while minimizing untoward effects.
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| - | GQ-16, A novel PPARgamma ligand, promotes insulin sensitization without weight gain.,Amato AA, Rajagopalan S, Lin JZ, Carvalho BM, Figueira AC, Lu J, Ayers SD, Mottin M, Silveira RL, Souza PC, Mourao RH, Saad MJ, Togashi M, Simeoni LA, Abdalla DS, Skaff MS, Polikarpov I, Lima MC, Galdino SL, Brennan RG, Baxter JD, Pitta IR, Webb P, Phillips KJ, Neves FA J Biol Chem. 2012 May 14. PMID:22584573<ref>PMID:22584573</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| - | <div class="pdbe-citations 3t03" style="background-color:#fffaf0;"></div>
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| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Peroxisome Proliferator-Activated Receptors|Peroxisome Proliferator-Activated Receptors]] | + | *[[Peroxisome proliferator-activated receptor 3D structures|Peroxisome proliferator-activated receptor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Histone acetyltransferase]] | |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Baxter, J D]] | + | [[Category: Large Structures]] |
| - | [[Category: Brennan, R G]] | + | [[Category: Baxter JD]] |
| - | [[Category: Phillips, K J]] | + | [[Category: Brennan RG]] |
| - | [[Category: Rajagopalan, S]] | + | [[Category: Phillips KJ]] |
| - | [[Category: Webb, P]] | + | [[Category: Rajagopalan S]] |
| - | [[Category: Ligand binding protein]]
| + | [[Category: Webb P]] |
| - | [[Category: Nucleus receptor]]
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| - | [[Category: Protein-drug complex]]
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| - | [[Category: Thiazolidinedione]]
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| - | [[Category: Transcription factor]]
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| - | [[Category: Transcription-transcription regulator complex]]
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