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| | ==Crystal structure of tetrameric RXRalpha-LBD complexed with partial agonist CBt-PMN== | | ==Crystal structure of tetrameric RXRalpha-LBD complexed with partial agonist CBt-PMN== |
| - | <StructureSection load='5zqu' size='340' side='right' caption='[[5zqu]], [[Resolution|resolution]] 2.60Å' scene=''> | + | <StructureSection load='5zqu' size='340' side='right'caption='[[5zqu]], [[Resolution|resolution]] 2.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5zqu]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZQU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ZQU FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5zqu]] 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=5ZQU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ZQU FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9HF:1-(3,5,5,8,8-pentamethyl-6,7-dihydronaphthalen-2-yl)benzotriazole-5-carboxylic+acid'>9HF</scene>, <scene name='pdbligand=BR:BROMIDE+ION'>BR</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]] 2.6003878Å</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=5zqu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zqu OCA], [http://pdbe.org/5zqu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5zqu RCSB], [http://www.ebi.ac.uk/pdbsum/5zqu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5zqu ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9HF:1-(3,5,5,8,8-pentamethyl-6,7-dihydronaphthalen-2-yl)benzotriazole-5-carboxylic+acid'>9HF</scene>, <scene name='pdbligand=BR:BROMIDE+ION'>BR</scene></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=5zqu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zqu OCA], [https://pdbe.org/5zqu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5zqu RCSB], [https://www.ebi.ac.uk/pdbsum/5zqu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5zqu ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[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> | + | [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> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5zqu" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5zqu" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Retinoid X receptor 3D structures|Retinoid X receptor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Arulmozhiraja, S]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Ikura, T]] | + | [[Category: Large Structures]] |
| - | [[Category: Ito, N]] | + | [[Category: Arulmozhiraja S]] |
| - | [[Category: Ito, S]] | + | [[Category: Ikura T]] |
| - | [[Category: Kakuta, H]] | + | [[Category: Ito N]] |
| - | [[Category: Matsuo, N]] | + | [[Category: Ito S]] |
| - | [[Category: Miyashita, Y]] | + | [[Category: Kakuta H]] |
| - | [[Category: Nakano, S]] | + | [[Category: Matsuo N]] |
| - | [[Category: Numoto, N]] | + | [[Category: Miyashita Y]] |
| - | [[Category: Shimizu, K]] | + | [[Category: Nakano S]] |
| - | [[Category: Tokiwa, H]] | + | [[Category: Numoto N]] |
| - | [[Category: Extended form]]
| + | [[Category: Shimizu K]] |
| - | [[Category: Multiple conformation]]
| + | [[Category: Tokiwa H]] |
| - | [[Category: Nuclear receptor]]
| + | |
| - | [[Category: Retinoid x receptor]]
| + | |
| - | [[Category: Transcription]]
| + | |
| 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]
Publication Abstract from PubMed
1-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino]benzotriazole-5 -carboxylic acid (CBt-PMN), a partial agonist of retinoid X receptor (RXR), has attracted attention due to its potential to treat type 2 diabetes and central nervous system diseases with reduced adverse effects of existing full agonists. Herein, we report the crystal structure of CBt-PMN-bound ligand-binding domain of human RXRalpha (hRXRalpha) and its biochemical characterization. Interestingly, the structure is a tetramer in nature, in which CBt-PMNs are clearly found binding in two different conformations. The dynamics of the hRXRalpha/CBt-PMN complex examined using molecular dynamics simulations suggest that the flexibility of the AF-2 interface depends on the conformation of the ligand. These facts reveal that the dual conformation of CBt-PMN in the complex is probably the reason behind its partial agonistic activity.
Dual conformation of the ligand induces the partial agonistic activity of retinoid X receptor alpha (RXRalpha).,Miyashita Y, Numoto N, Arulmozhiraja S, Nakano S, Matsuo N, Shimizu K, Shibahara O, Fujihara M, Kakuta H, Ito S, Ikura T, Ito N, Tokiwa H FEBS Lett. 2019 Jan;593(2):242-250. doi: 10.1002/1873-3468.13301. Epub 2018 Dec, 21. PMID:30565665[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
- ↑ Miyashita Y, Numoto N, Arulmozhiraja S, Nakano S, Matsuo N, Shimizu K, Shibahara O, Fujihara M, Kakuta H, Ito S, Ikura T, Ito N, Tokiwa H. Dual conformation of the ligand induces the partial agonistic activity of retinoid X receptor alpha (RXRalpha). FEBS Lett. 2019 Jan;593(2):242-250. doi: 10.1002/1873-3468.13301. Epub 2018 Dec, 21. PMID:30565665 doi:http://dx.doi.org/10.1002/1873-3468.13301
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