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| | ==Crystal structure of the orphan nuclear receptor RORalpha ligand-binding domain in complex with 4alpha-caboxyl, 4beta-methyl-zymosterol (4ACD8)== | | ==Crystal structure of the orphan nuclear receptor RORalpha ligand-binding domain in complex with 4alpha-caboxyl, 4beta-methyl-zymosterol (4ACD8)== |
| - | <StructureSection load='4s15' size='340' side='right' caption='[[4s15]], [[Resolution|resolution]] 1.90Å' scene=''> | + | <StructureSection load='4s15' size='340' side='right'caption='[[4s15]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4s15]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4S15 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4S15 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4s15]] 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=4S15 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4S15 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4D8:(3BETA,4ALPHA,5BETA,14BETA)-3-HYDROXY-4-METHYLCHOLESTA-8,24-DIENE-4-CARBOXYLIC+ACID'>4D8</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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]] 1.897Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4s14|4s14]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4D8:(3BETA,4ALPHA,5BETA,14BETA)-3-HYDROXY-4-METHYLCHOLESTA-8,24-DIENE-4-CARBOXYLIC+ACID'>4D8</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=4s15 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4s15 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4s15 RCSB], [http://www.ebi.ac.uk/pdbsum/4s15 PDBsum]</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=4s15 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4s15 OCA], [https://pdbe.org/4s15 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4s15 RCSB], [https://www.ebi.ac.uk/pdbsum/4s15 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4s15 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/RORA_HUMAN RORA_HUMAN]] Orphan nuclear receptor. Binds DNA as a monomer to hormone response elements (HRE) containing a single core motif half-site preceded by a short A-T-rich sequence. This isomer binds to the consensus sequence 5'-[AT][TA]A[AT][CGT]TAGGTCA-3'. Regulates a number of genes involved in lipid metabolism such as apolipoproteins AI, APOA5, CIII, CYP71 and PPARgamma, in cerebellum and photoreceptor development including PCP2, OPN1SW, OPN1SM AND ARR3, in circadian rhythm with BMAL1, and skeletal muscle development with MYOD1. Possible receptor for cholesterol or one of its derivatives.<ref>PMID:9862959</ref> <ref>PMID:11554739</ref> <ref>PMID:11053433</ref> <ref>PMID:14570920</ref> <ref>PMID:15790933</ref> <ref>PMID:15781255</ref> <ref>PMID:17512500</ref> <ref>PMID:18658046</ref> <ref>PMID:18005000</ref> <ref>PMID:12467577</ref> [[http://www.uniprot.org/uniprot/NRIP1_HUMAN NRIP1_HUMAN]] Modulates transcriptional activation by steroid receptors such as NR3C1, NR3C2 and ESR1. Also modulates transcriptional repression by nuclear hormone receptors.<ref>PMID:7641693</ref> <ref>PMID:10364267</ref> <ref>PMID:11509661</ref> <ref>PMID:11518808</ref> <ref>PMID:12554755</ref> <ref>PMID:15060175</ref> | + | [https://www.uniprot.org/uniprot/RORA_HUMAN RORA_HUMAN] Orphan nuclear receptor. Binds DNA as a monomer to hormone response elements (HRE) containing a single core motif half-site preceded by a short A-T-rich sequence. This isomer binds to the consensus sequence 5'-[AT][TA]A[AT][CGT]TAGGTCA-3'. Regulates a number of genes involved in lipid metabolism such as apolipoproteins AI, APOA5, CIII, CYP71 and PPARgamma, in cerebellum and photoreceptor development including PCP2, OPN1SW, OPN1SM AND ARR3, in circadian rhythm with BMAL1, and skeletal muscle development with MYOD1. Possible receptor for cholesterol or one of its derivatives.<ref>PMID:9862959</ref> <ref>PMID:11554739</ref> <ref>PMID:11053433</ref> <ref>PMID:14570920</ref> <ref>PMID:15790933</ref> <ref>PMID:15781255</ref> <ref>PMID:17512500</ref> <ref>PMID:18658046</ref> <ref>PMID:18005000</ref> <ref>PMID:12467577</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
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| - | Mice deficient in the nuclear hormone receptor RORgammat have defective development of thymocytes, lymphoid organs, Th17 cells, and type 3 innate lymphoid cells. RORgammat binds to oxysterols derived from cholesterol catabolism, but it is not clear whether these are its natural ligands. Here, we show that sterol lipids are necessary and sufficient to drive RORgammat-dependent transcription. We combined overexpression, RNAi, and genetic deletion of metabolic enzymes to study RORgamma-dependent transcription. Our results are consistent with the RORgammat ligand(s) being a cholesterol biosynthetic intermediate (CBI) downstream of lanosterol and upstream of zymosterol. Analysis of lipids bound to RORgamma identified molecules with molecular weights consistent with CBIs. Furthermore, CBIs stabilized the RORgamma ligand-binding domain and induced coactivator recruitment. Genetic deletion of metabolic enzymes upstream of the RORgammat-ligand(s) affected the development of lymph nodes and Th17 cells. Our data suggest that CBIs play a role in lymphocyte development potentially through regulation of RORgammat.
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| - | Identification of Natural RORgamma Ligands that Regulate the Development of Lymphoid Cells.,Santori FR, Huang P, van de Pavert SA, Douglass EF Jr, Leaver DJ, Haubrich BA, Keber R, Lorbek G, Konijn T, Rosales BN, Rozman D, Horvat S, Rahier A, Mebius RE, Rastinejad F, Nes WD, Littman DR Cell Metab. 2015 Feb 3;21(2):286-97. doi: 10.1016/j.cmet.2015.01.004. PMID:25651181<ref>PMID:25651181</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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| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Huang, P]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Littman, D R]] | + | [[Category: Large Structures]] |
| - | [[Category: Rastinejad, F]] | + | [[Category: Huang P]] |
| - | [[Category: Santori, F R]] | + | [[Category: Littman DR]] |
| - | [[Category: Transcription]] | + | [[Category: Rastinejad F]] |
| - | [[Category: Transcription factor]] | + | [[Category: Santori FR]] |
| Structural highlights
Function
RORA_HUMAN Orphan nuclear receptor. Binds DNA as a monomer to hormone response elements (HRE) containing a single core motif half-site preceded by a short A-T-rich sequence. This isomer binds to the consensus sequence 5'-[AT][TA]A[AT][CGT]TAGGTCA-3'. Regulates a number of genes involved in lipid metabolism such as apolipoproteins AI, APOA5, CIII, CYP71 and PPARgamma, in cerebellum and photoreceptor development including PCP2, OPN1SW, OPN1SM AND ARR3, in circadian rhythm with BMAL1, and skeletal muscle development with MYOD1. Possible receptor for cholesterol or one of its derivatives.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]
References
- ↑ Lau P, Bailey P, Dowhan DH, Muscat GE. Exogenous expression of a dominant negative RORalpha1 vector in muscle cells impairs differentiation: RORalpha1 directly interacts with p300 and myoD. Nucleic Acids Res. 1999 Jan 15;27(2):411-20. PMID:9862959
- ↑ Sundvold H, Lien S. Identification of a novel peroxisome proliferator-activated receptor (PPAR) gamma promoter in man and transactivation by the nuclear receptor RORalpha1. Biochem Biophys Res Commun. 2001 Sep 21;287(2):383-90. PMID:11554739 doi:http://dx.doi.org/10.1006/bbrc.2001.5602
- ↑ Raspe E, Duez H, Gervois P, Fievet C, Fruchart JC, Besnard S, Mariani J, Tedgui A, Staels B. Transcriptional regulation of apolipoprotein C-III gene expression by the orphan nuclear receptor RORalpha. J Biol Chem. 2001 Jan 26;276(4):2865-71. Epub 2000 Oct 26. PMID:11053433 doi:http://dx.doi.org/10.1074/jbc.M004982200
- ↑ Moraitis AN, Giguere V. The co-repressor hairless protects RORalpha orphan nuclear receptor from proteasome-mediated degradation. J Biol Chem. 2003 Dec 26;278(52):52511-8. Epub 2003 Oct 21. PMID:14570920 doi:http://dx.doi.org/10.1074/jbc.M308152200
- ↑ Genoux A, Dehondt H, Helleboid-Chapman A, Duhem C, Hum DW, Martin G, Pennacchio LA, Staels B, Fruchart-Najib J, Fruchart JC. Transcriptional regulation of apolipoprotein A5 gene expression by the nuclear receptor RORalpha. Arterioscler Thromb Vasc Biol. 2005 Jun;25(6):1186-92. Epub 2005 Mar 24. PMID:15790933 doi:http://dx.doi.org/10.1161/01.ATV.0000163841.85333.83
- ↑ Lind U, Nilsson T, McPheat J, Stromstedt PE, Bamberg K, Balendran C, Kang D. Identification of the human ApoAV gene as a novel RORalpha target gene. Biochem Biophys Res Commun. 2005 Apr 29;330(1):233-41. PMID:15781255 doi:http://dx.doi.org/10.1016/j.bbrc.2005.02.151
- ↑ Lechtken A, Hornig M, Werz O, Corvey N, Zundorf I, Dingermann T, Brandes R, Steinhilber D. Extracellular signal-regulated kinase-2 phosphorylates RORalpha4 in vitro. Biochem Biophys Res Commun. 2007 Jul 6;358(3):890-6. Epub 2007 May 11. PMID:17512500 doi:http://dx.doi.org/10.1016/j.bbrc.2007.05.016
- ↑ Kim EJ, Yoo YG, Yang WK, Lim YS, Na TY, Lee IK, Lee MO. Transcriptional activation of HIF-1 by RORalpha and its role in hypoxia signaling. Arterioscler Thromb Vasc Biol. 2008 Oct;28(10):1796-802. doi:, 10.1161/ATVBAHA.108.171546. Epub 2008 Jul 24. PMID:18658046 doi:http://dx.doi.org/10.1161/ATVBAHA.108.171546
- ↑ Duplus E, Gras C, Soubeyre V, Vodjdani G, Lemaigre-Dubreuil Y, Brugg B. Phosphorylation and transcriptional activity regulation of retinoid-related orphan receptor alpha 1 by protein kinases C. J Neurochem. 2008 Mar;104(5):1321-32. Epub 2007 Nov 10. PMID:18005000 doi:http://dx.doi.org/10.1111/j.1471-4159.2007.05074.x
- ↑ Kallen JA, Schlaeppi JM, Bitsch F, Geisse S, Geiser M, Delhon I, Fournier B. X-ray structure of the hRORalpha LBD at 1.63 A: structural and functional data that cholesterol or a cholesterol derivative is the natural ligand of RORalpha. Structure. 2002 Dec;10(12):1697-707. PMID:12467577
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