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| | ==Crystal structure of multi-domain RAR-beta-RXR-alpha heterodimer on DNA== | | ==Crystal structure of multi-domain RAR-beta-RXR-alpha heterodimer on DNA== |
| - | <StructureSection load='5uan' size='340' side='right' caption='[[5uan]], [[Resolution|resolution]] 3.51Å' scene=''> | + | <StructureSection load='5uan' size='340' side='right'caption='[[5uan]], [[Resolution|resolution]] 3.51Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5uan]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UAN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UAN FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5uan]] is a 6 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=5UAN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5UAN FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9CR:(9CIS)-RETINOIC+ACID'>9CR</scene>, <scene name='pdbligand=REA:RETINOIC+ACID'>REA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 3.508Å</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=5uan FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uan OCA], [http://pdbe.org/5uan PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5uan RCSB], [http://www.ebi.ac.uk/pdbsum/5uan PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5uan ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9CR:(9CIS)-RETINOIC+ACID'>9CR</scene>, <scene name='pdbligand=REA:RETINOIC+ACID'>REA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=5uan FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uan OCA], [https://pdbe.org/5uan PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5uan RCSB], [https://www.ebi.ac.uk/pdbsum/5uan PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5uan 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> [[http://www.uniprot.org/uniprot/RARB_HUMAN RARB_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 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 or presence of hormone ligand, acts mainly as an activator of gene expression due to weak binding to corepressors. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function.<ref>PMID:12554770</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;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Assessing the physical connections and allosteric communications in multi-domain nuclear receptor (NR) polypeptides has remained challenging, with few crystal structures available to show their overall structural organizations. Here we report the quaternary architecture of multi-domain retinoic acid receptor beta-retinoic X receptor alpha (RARbeta-RXRalpha) heterodimer bound to DNA, ligands and coactivator peptides, examined through crystallographic, hydrogen-deuterium exchange mass spectrometry, mutagenesis and functional studies. The RARbeta ligand-binding domain (LBD) and DNA-binding domain (DBD) are physically connected to foster allosteric signal transmission between them. Direct comparisons among all the multi-domain NRs studied crystallographically to date show significant variations within their quaternary architectures, rather than a common architecture adhering to strict rules. RXR remains flexible and adaptive by maintaining loosely organized domains, while its heterodimerization partners use a surface patch on their LBDs to form domain-domain interactions with DBDs.Nuclear receptors (NR) are multidomain proteins, which makes their crystallization challenging. Here the authors present the crystal structure of the retinoic acid receptor beta-retinoic X receptor alpha (RARbeta-RXRalpha) heterodimer bound to DNA, ligands and coactivator peptides, which shows that NR quaternary architectures are variable. |
| | + | |
| | + | The quaternary architecture of RARbeta-RXRalpha heterodimer facilitates domain-domain signal transmission.,Chandra V, Wu D, Li S, Potluri N, Kim Y, Rastinejad F Nat Commun. 2017 Oct 11;8(1):868. doi: 10.1038/s41467-017-00981-y. PMID:29021580<ref>PMID:29021580</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 5uan" 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: Chandra, V]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Kim, Y]] | + | [[Category: Large Structures]] |
| - | [[Category: Rastinejad, F]] | + | [[Category: Chandra V]] |
| - | [[Category: Wu, D]] | + | [[Category: Kim Y]] |
| - | [[Category: Nuclear receptor]] | + | [[Category: Rastinejad F]] |
| - | [[Category: Protein-dna complex]] | + | [[Category: Wu D]] |
| - | [[Category: Transcription]]
| + | |
| - | [[Category: Transcription-dna complex]]
| + | |
| 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
Assessing the physical connections and allosteric communications in multi-domain nuclear receptor (NR) polypeptides has remained challenging, with few crystal structures available to show their overall structural organizations. Here we report the quaternary architecture of multi-domain retinoic acid receptor beta-retinoic X receptor alpha (RARbeta-RXRalpha) heterodimer bound to DNA, ligands and coactivator peptides, examined through crystallographic, hydrogen-deuterium exchange mass spectrometry, mutagenesis and functional studies. The RARbeta ligand-binding domain (LBD) and DNA-binding domain (DBD) are physically connected to foster allosteric signal transmission between them. Direct comparisons among all the multi-domain NRs studied crystallographically to date show significant variations within their quaternary architectures, rather than a common architecture adhering to strict rules. RXR remains flexible and adaptive by maintaining loosely organized domains, while its heterodimerization partners use a surface patch on their LBDs to form domain-domain interactions with DBDs.Nuclear receptors (NR) are multidomain proteins, which makes their crystallization challenging. Here the authors present the crystal structure of the retinoic acid receptor beta-retinoic X receptor alpha (RARbeta-RXRalpha) heterodimer bound to DNA, ligands and coactivator peptides, which shows that NR quaternary architectures are variable.
The quaternary architecture of RARbeta-RXRalpha heterodimer facilitates domain-domain signal transmission.,Chandra V, Wu D, Li S, Potluri N, Kim Y, Rastinejad F Nat Commun. 2017 Oct 11;8(1):868. doi: 10.1038/s41467-017-00981-y. PMID:29021580[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
- ↑ Chandra V, Wu D, Li S, Potluri N, Kim Y, Rastinejad F. The quaternary architecture of RARbeta-RXRalpha heterodimer facilitates domain-domain signal transmission. Nat Commun. 2017 Oct 11;8(1):868. doi: 10.1038/s41467-017-00981-y. PMID:29021580 doi:http://dx.doi.org/10.1038/s41467-017-00981-y
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