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- | {{STRUCTURE_2nll| PDB=2nll | SCENE= }} | |
- | ===RETINOID X RECEPTOR-THYROID HORMONE RECEPTOR DNA-BINDING DOMAIN HETERODIMER BOUND TO THYROID RESPONSE ELEMENT DNA=== | |
- | {{ABSTRACT_PUBMED_7746322}} | |
| | | |
- | ==Disease== | + | ==RETINOID X RECEPTOR-THYROID HORMONE RECEPTOR DNA-BINDING DOMAIN HETERODIMER BOUND TO THYROID RESPONSE ELEMENT DNA== |
- | [[http://www.uniprot.org/uniprot/THB1_HUMAN THB1_HUMAN]] Defects in THRB are the cause of generalized thyroid hormone resistance (GTHR) [MIM:[http://omim.org/entry/188570 188570]]. GTHR is a disease characterized by goiter, abnormal mental functions, increased susceptibility to infections, abnormal growth and bone maturation, tachycardia and deafness. Affected individuals may also have attention deficit-hyperactivity disorders (ADHD) and language difficulties. GTHR patients also have high levels of circulating thyroid hormones (T3-T4), with normal or slightly elevated thyroid stimulating hormone (TSH).<ref>PMID:2510172</ref><ref>PMID:2153155</ref><ref>PMID:1846005</ref><ref>PMID:1661299</ref><ref>PMID:1653889</ref><ref>PMID:1563081</ref><ref>PMID:1314846</ref><ref>PMID:1619012</ref><ref>PMID:1587388</ref><ref>PMID:1324420</ref><ref>PMID:8514853</ref><ref>PMID:8175986</ref><ref>PMID:7833659</ref><ref>PMID:8664910</ref><ref>PMID:8889584</ref><ref>PMID:10660344</ref><ref>PMID:16804041</ref><ref>PMID:19268523</ref> Defects in THRB are the cause of generalized thyroid hormone resistance autosomal recessive (GTHRAR) [MIM:[http://omim.org/entry/274300 274300]]. An autosomal recessive disorder characterized by goiter, clinical euthyroidism, end-organ unresponsiveness to thyroid hormone, abnormal growth and bone maturation, and deafness. Patients also have high levels of circulating thyroid hormones, with elevated thyroid stimulating hormone. Defects in THRB are the cause of selective pituitary thyroid hormone resistance (PRTH) [MIM:[http://omim.org/entry/145650 145650]]; also known as familial hyperthyroidism due to inappropriate thyrotropin secretion. PRTH is a variant form of thyroid hormone resistance and is characterized by clinical hyperthyroidism, with elevated free thyroid hormones, but inappropriately normal serum TSH. Unlike GRTH, where the syndrome usually segregates with a dominant allele, the mode of inheritance in PRTH has not been established.<ref>PMID:7528740</ref><ref>PMID:8381821</ref> | + | <StructureSection load='2nll' size='340' side='right'caption='[[2nll]], [[Resolution|resolution]] 1.90Å' scene=''> |
- | | + | == Structural highlights == |
- | ==Function== | + | <table><tr><td colspan='2'>[[2nll]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. The November 2012 RCSB PDB [https://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Vitamin D Receptor'' by David Goodsell is [https://dx.doi.org/10.2210/rcsb_pdb/mom_2012_11 10.2210/rcsb_pdb/mom_2012_11]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2NLL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2NLL FirstGlance]. <br> |
- | [[http://www.uniprot.org/uniprot/THB1_HUMAN THB1_HUMAN]] High affinity receptor for triiodothyronine.<ref>PMID:17418816</ref> [[http://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> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9Å</td></tr> |
- | | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5IU:5-IODO-2-DEOXYURIDINE-5-MONOPHOSPHATE'>5IU</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
- | ==About this Structure== | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2nll FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nll OCA], [https://pdbe.org/2nll PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2nll RCSB], [https://www.ebi.ac.uk/pdbsum/2nll PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2nll ProSAT]</span></td></tr> |
- | [[2nll]] 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=2NLL OCA]. | + | </table> |
| + | == Function == |
| + | [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 == |
| + | [[Image:Consurf_key_small.gif|200px|right]] |
| + | Check<jmol> |
| + | <jmolCheckbox> |
| + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/nl/2nll_consurf.spt"</scriptWhenChecked> |
| + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| + | <text>to colour the structure by Evolutionary Conservation</text> |
| + | </jmolCheckbox> |
| + | </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=2nll ConSurf]. |
| + | <div style="clear:both"></div> |
| | | |
| ==See Also== | | ==See Also== |
- | *[[Hormone|Hormone]] | + | *[[Thyroid hormone receptor 3D structures|Thyroid hormone receptor 3D structures]] |
- | | + | == References == |
- | ==Reference== | + | <references/> |
- | <ref group="xtra">PMID:007746322</ref><ref group="xtra">PMID:014702633</ref><ref group="xtra">PMID:015048824</ref><ref group="xtra">PMID:017397256</ref><references group="xtra"/><references/>
| + | __TOC__ |
| + | </StructureSection> |
| [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
- | [[Category: Evans, R M.]] | + | [[Category: Large Structures]] |
- | [[Category: Perlmann, T.]] | + | [[Category: RCSB PDB Molecule of the Month]] |
- | [[Category: Rastinejad, F.]] | + | [[Category: Vitamin D Receptor]] |
- | [[Category: Sigler, P B.]] | + | [[Category: Evans RM]] |
- | [[Category: Dna-binding]] | + | [[Category: Perlmann T]] |
- | [[Category: Multigene family]] | + | [[Category: Rastinejad F]] |
- | [[Category: Nuclear protein]] | + | [[Category: Sigler PB]] |
- | [[Category: Receptor]]
| + | |
- | [[Category: Transcription-dna complex]]
| + | |
- | [[Category: Zinc- finger]]
| + | |
| Structural highlights
Function
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.[1] [2] [3] [4]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
See Also
References
- ↑ Gorla-Bajszczak A, Juge-Aubry C, Pernin A, Burger AG, Meier CA. Conserved amino acids in the ligand-binding and tau(i) domains of the peroxisome proliferator-activated receptor alpha are necessary for heterodimerization with RXR. Mol Cell Endocrinol. 1999 Jan 25;147(1-2):37-47. PMID:10195690
- ↑ Harish S, Ashok MS, Khanam T, Rangarajan PN. Serine 27, a human retinoid X receptor alpha residue, phosphorylated by protein kinase A is essential for cyclicAMP-mediated downregulation of RXRalpha function. Biochem Biophys Res Commun. 2000 Dec 29;279(3):853-7. PMID:11162439 doi:10.1006/bbrc.2000.4043
- ↑ Tsutsumi T, Suzuki T, Shimoike T, Suzuki R, Moriya K, Shintani Y, Fujie H, Matsuura Y, Koike K, Miyamura T. Interaction of hepatitis C virus core protein with retinoid X receptor alpha modulates its transcriptional activity. Hepatology. 2002 Apr;35(4):937-46. PMID:11915042 doi:10.1053/jhep.2002.32470
- ↑ Santos NC, Kim KH. Activity of retinoic acid receptor-alpha is directly regulated at its protein kinase A sites in response to follicle-stimulating hormone signaling. Endocrinology. 2010 May;151(5):2361-72. doi: 10.1210/en.2009-1338. Epub 2010 Mar , 9. PMID:20215566 doi:10.1210/en.2009-1338
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