3h0a

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<StructureSection load='3h0a' size='340' side='right'caption='[[3h0a]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
<StructureSection load='3h0a' size='340' side='right'caption='[[3h0a]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3h0a]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3H0A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3H0A FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3h0a]] 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=3H0A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3H0A FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9RA:4-[1-(3,5,5,8,8-PENTAMETHYL-5,6,7,8-TETRAHYDRONAPHTHALEN-2-YL)ETHENYL]BENZOIC+ACID'>9RA</scene>, <scene name='pdbligand=D30:[(4-{[2-(PENT-2-YN-1-YLOXY)-4-{[4-(TRIFLUOROMETHYL)PHENOXY]METHYL}PHENYL]SULFANYL}-5,6,7,8-TETRAHYDRONAPHTHALEN-1-YL)OXY]ACETIC+ACID'>D30</scene></td></tr>
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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]] 2.1&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RXRA, NR2B1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), PPARG, NR1C3 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9RA:4-[1-(3,5,5,8,8-PENTAMETHYL-5,6,7,8-TETRAHYDRONAPHTHALEN-2-YL)ETHENYL]BENZOIC+ACID'>9RA</scene>, <scene name='pdbligand=D30:[(4-{[2-(PENT-2-YN-1-YLOXY)-4-{[4-(TRIFLUOROMETHYL)PHENOXY]METHYL}PHENYL]SULFANYL}-5,6,7,8-TETRAHYDRONAPHTHALEN-1-YL)OXY]ACETIC+ACID'>D30</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Histone_acetyltransferase Histone acetyltransferase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.48 2.3.1.48] </span></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=3h0a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3h0a OCA], [https://pdbe.org/3h0a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3h0a RCSB], [https://www.ebi.ac.uk/pdbsum/3h0a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3h0a 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=3h0a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3h0a OCA], [https://pdbe.org/3h0a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3h0a RCSB], [https://www.ebi.ac.uk/pdbsum/3h0a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3h0a ProSAT]</span></td></tr>
</table>
</table>
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== Disease ==
 
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[[https://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 ==
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[[https://www.uniprot.org/uniprot/RXRA_HUMAN RXRA_HUMAN]] Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes.<ref>PMID:10195690</ref> <ref>PMID:11162439</ref> <ref>PMID:11915042</ref> <ref>PMID:20215566</ref> [[https://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>
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[https://www.uniprot.org/uniprot/RXRA_HUMAN RXRA_HUMAN] Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes.<ref>PMID:10195690</ref> <ref>PMID:11162439</ref> <ref>PMID:11915042</ref> <ref>PMID:20215566</ref>
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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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=3h0a ConSurf].
</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=3h0a 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 discovery and optimization of a series of potent PPARdelta full agonists with partial agonistic activity against PPARgamma is described.
 
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Identification of a PPARdelta agonist with partial agonistic activity on PPARgamma.,Connors RV, Wang Z, Harrison M, Zhang A, Wanska M, Hiscock S, Fox B, Dore M, Labelle M, Sudom A, Johnstone S, Liu J, Walker NP, Chai A, Siegler K, Li Y, Coward P Bioorg Med Chem Lett. 2009 Jul 1;19(13):3550-4. Epub 2009 May 9. PMID:19464171<ref>PMID:19464171</ref>
 
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 
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</div>
 
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<div class="pdbe-citations 3h0a" style="background-color:#fffaf0;"></div>
 
==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Histone acetyltransferase]]
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[[Category: Homo sapiens]]
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[[Category: Human]]
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[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Sudom, A]]
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[[Category: Sudom A]]
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[[Category: Walker, N P]]
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[[Category: Walker NP]]
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[[Category: Wang, Z]]
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[[Category: Wang Z]]
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[[Category: Activator]]
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[[Category: Acyltransferase]]
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[[Category: Complex]]
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[[Category: Diabetes mellitus]]
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[[Category: Disease mutation]]
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[[Category: Dna-binding]]
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[[Category: Growth factor receptor]]
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[[Category: Hormone]]
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[[Category: Host-virus interaction]]
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[[Category: Isopeptide bond]]
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[[Category: Metal-binding]]
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[[Category: Nuclear receptor fold]]
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[[Category: Nucleus]]
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[[Category: Obesity]]
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[[Category: Phosphoprotein]]
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[[Category: Ppar]]
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[[Category: Proto-oncogene]]
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[[Category: Receptor]]
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[[Category: Transcription]]
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[[Category: Transcription regulation]]
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[[Category: Transferase]]
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[[Category: Zinc-finger]]
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Current revision

Crystal Structure of Peroxisome Proliferator-Activated Receptor Gamma (PPARg) and Retinoic Acid Receptor Alpha (RXRa) in Complex with 9-cis Retinoic Acid, Co-activator Peptide, and a Partial Agonist

PDB ID 3h0a

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