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1xdk

From Proteopedia

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Revision as of 09:54, 6 January 2021

Crystal Structure of the RARbeta/RXRalpha Ligand Binding Domain Heterodimer in Complex with 9-cis Retinoic Acid and a Fragment of the TRAP220 Coactivator

Structural highlights

1xdk is a 8 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	1dkf
Gene:	Rxra, Nr2b1 (LK3 transgenic mice), Rarb, Nr1b2 (LK3 transgenic mice)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[RXRA_MOUSE] 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] [MED1_MOUSE] Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Essential for embryogenesis, including development of the central nervous system, heart, liver and placenta and for erythropoiesis. Also required for normal transcriptional control of thyroid-stimulating hormone beta (TSHB) in the pituitary.^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11] ^[12] ^[13] [RARB_MOUSE] 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. In the absence of ligand, acts mainly as an activator of gene expression due to weak binding to corepressors (By similarity). In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Retinoid receptors (RARs and RXRs) are ligand-activated transcription factors that regulate the transcription of target genes by recruiting coregulator complexes at cognate promoters. To understand the effects of heterodimerization and ligand binding on coactivator recruitment, we solved the crystal structure of the complex between the RARbeta/RXRalpha ligand-binding domain heterodimer, its 9-cis retinoic acid ligand, and an LXXLL-containing peptide (termed NR box 2) derived from the nuclear receptor interaction domain (NID) of the TRAP220 coactivator. In parallel, we measured the binding affinities of the isolated NR box 2 peptide or the full-length NID of the coactivator SRC-1 for retinoid receptors in the presence of various types of ligands. Our correlative analysis of three-dimensional structures and fluorescence data reveals that heterodimerization does not significantly alter the structure of individual subunits or their intrinsic capacity to interact with NR box 2. Similarly, we show that the ability of a protomer to recruit NR box 2 does not vary as a function of the ligand binding status of the partner receptor. In contrast, the strength of the overall association between the heterodimer and the full-length SRC-1 NID is dictated by the combinatorial action of RAR and RXR ligands, the simultaneous presence of the two receptor agonists being required for highest binding affinity. We identified an LXXLL peptide-driven mechanism by which the concerted reorientation of three phenylalanine side chains generates an "aromatic clamp" that locks the RXR activation helix H12 in the transcriptionally active conformation. Finally, we show how variations of helix H11-ligand interactions can alter the communication pathway linking helices H11, H12, and the connecting loop L11-12 to the coactivator-binding site. Together, our results reveal molecular and structural features that impact on the ligand-dependent interaction of the RAR/RXR heterodimer with nuclear receptor coactivators.

Characterization of the interaction between retinoic acid receptor/retinoid X receptor (RAR/RXR) heterodimers and transcriptional coactivators through structural and fluorescence anisotropy studies.,Pogenberg V, Guichou JF, Vivat-Hannah V, Kammerer S, Perez E, Germain P, de Lera AR, Gronemeyer H, Royer CA, Bourguet W J Biol Chem. 2005 Jan 14;280(2):1625-33. Epub 2004 Nov 4. PMID:15528208^[14]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Leid M, Kastner P, Lyons R, Nakshatri H, Saunders M, Zacharewski T, Chen JY, Staub A, Garnier JM, Mader S, et al.. Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently. Cell. 1992 Jan 24;68(2):377-95. PMID:1310259
↑ Adam-Stitah S, Penna L, Chambon P, Rochette-Egly C. Hyperphosphorylation of the retinoid X receptor alpha by activated c-Jun NH2-terminal kinases. J Biol Chem. 1999 Jul 2;274(27):18932-41. PMID:10383391
↑ Bastien J, Adam-Stitah S, Plassat JL, Chambon P, Rochette-Egly C. The phosphorylation site located in the A region of retinoic X receptor alpha is required for the antiproliferative effect of retinoic acid (RA) and the activation of RA target genes in F9 cells. J Biol Chem. 2002 Aug 9;277(32):28683-9. Epub 2002 May 24. PMID:12032153 doi:10.1074/jbc.M203623200
↑ Zhu Y, Qi C, Jain S, Rao MS, Reddy JK. Isolation and characterization of PBP, a protein that interacts with peroxisome proliferator-activated receptor. J Biol Chem. 1997 Oct 10;272(41):25500-6. PMID:9325263
↑ Landles C, Chalk S, Steel JH, Rosewell I, Spencer-Dene B, Lalani el-N, Parker MG. The thyroid hormone receptor-associated protein TRAP220 is required at distinct embryonic stages in placental, cardiac, and hepatic development. Mol Endocrinol. 2003 Dec;17(12):2418-35. Epub 2003 Sep 18. PMID:14500757 doi:http://dx.doi.org/10.1210/me.2003-0097
↑ Ito M, Yuan CX, Okano HJ, Darnell RB, Roeder RG. Involvement of the TRAP220 component of the TRAP/SMCC coactivator complex in embryonic development and thyroid hormone action. Mol Cell. 2000 Apr;5(4):683-93. PMID:10882104
↑ Ge K, Guermah M, Yuan CX, Ito M, Wallberg AE, Spiegelman BM, Roeder RG. Transcription coactivator TRAP220 is required for PPAR gamma 2-stimulated adipogenesis. Nature. 2002 May 30;417(6888):563-7. PMID:12037571 doi:10.1038/417563a
↑ Kang YK, Guermah M, Yuan CX, Roeder RG. The TRAP/Mediator coactivator complex interacts directly with estrogen receptors alpha and beta through the TRAP220 subunit and directly enhances estrogen receptor function in vitro. Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2642-7. Epub 2002 Feb 26. PMID:11867769 doi:10.1073/pnas.261715899
↑ Wallberg AE, Yamamura S, Malik S, Spiegelman BM, Roeder RG. Coordination of p300-mediated chromatin remodeling and TRAP/mediator function through coactivator PGC-1alpha. Mol Cell. 2003 Nov;12(5):1137-49. PMID:14636573
↑ Jia Y, Qi C, Kashireddi P, Surapureddi S, Zhu YJ, Rao MS, Le Roith D, Chambon P, Gonzalez FJ, Reddy JK. Transcription coactivator PBP, the peroxisome proliferator-activated receptor (PPAR)-binding protein, is required for PPARalpha-regulated gene expression in liver. J Biol Chem. 2004 Jun 4;279(23):24427-34. Epub 2004 Mar 29. PMID:15150259 doi:http://dx.doi.org/10.1074/jbc.M402391200
↑ Malik S, Guermah M, Yuan CX, Wu W, Yamamura S, Roeder RG. Structural and functional organization of TRAP220, the TRAP/mediator subunit that is targeted by nuclear receptors. Mol Cell Biol. 2004 Sep;24(18):8244-54. PMID:15340084 doi:10.1128/MCB.24.18.8244-8254.2004
↑ Park SW, Li G, Lin YP, Barrero MJ, Ge K, Roeder RG, Wei LN. Thyroid hormone-induced juxtaposition of regulatory elements/factors and chromatin remodeling of Crabp1 dependent on MED1/TRAP220. Mol Cell. 2005 Sep 2;19(5):643-53. PMID:16137621 doi:http://dx.doi.org/S1097-2765(05)01526-1
↑ Stumpf M, Waskow C, Krotschel M, van Essen D, Rodriguez P, Zhang X, Guyot B, Roeder RG, Borggrefe T. The mediator complex functions as a coactivator for GATA-1 in erythropoiesis via subunit Med1/TRAP220. Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18504-9. Epub 2006 Nov 28. PMID:17132730 doi:http://dx.doi.org/0604494103
↑ Pogenberg V, Guichou JF, Vivat-Hannah V, Kammerer S, Perez E, Germain P, de Lera AR, Gronemeyer H, Royer CA, Bourguet W. Characterization of the interaction between retinoic acid receptor/retinoid X receptor (RAR/RXR) heterodimers and transcriptional coactivators through structural and fluorescence anisotropy studies. J Biol Chem. 2005 Jan 14;280(2):1625-33. Epub 2004 Nov 4. PMID:15528208 doi:http://dx.doi.org/10.1074/jbc.M409302200

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1xdk"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of the RARbeta/RXRalpha Ligand Binding Domain Heterodimer in Complex with 9-cis Retinoic Acid and a Fragment of the TRAP220 Coactivator==
-<StructureSection load='1xdk' size='340' side='right' caption='[[1xdk]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
+<StructureSection load='1xdk' size='340' side='right'caption='[[1xdk]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1xdk]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XDK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1XDK FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1xdk]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XDK OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=1XDK 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></td></tr>
+</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></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1dkf|1dkf]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1dkf|1dkf]]</div></td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Rxra, Nr2b1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice]), Rarb, Nr1b2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</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=1xdk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xdk OCA], [http://pdbe.org/1xdk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1xdk RCSB], [http://www.ebi.ac.uk/pdbsum/1xdk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1xdk ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=1xdk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xdk OCA], [http://pdbe.org/1xdk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1xdk RCSB], [http://www.ebi.ac.uk/pdbsum/1xdk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1xdk ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 15: / Line 15: @@
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/xd/1xdk_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/xd/1xdk_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
@@ Line 30: / Line 30: @@
 </div>
 <div class="pdbe-citations 1xdk" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Retinoic acid receptor 3D structures|Retinoic acid receptor 3D structures]]
+*[[Retinoid X receptor 3D structures|Retinoid X receptor 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Lk3 transgenic mice]]
 [[Category: Bourguet, W]]

1xdk

From Proteopedia

Revision as of 09:54, 6 January 2021

Crystal Structure of the RARbeta/RXRalpha Ligand Binding Domain Heterodimer in Complex with 9-cis Retinoic Acid and a Fragment of the TRAP220 Coactivator

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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