7qaa

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of RARalpha/RXRalpha ligand binding domain heterodimer in complex with BMS614 and oleic acid

Structural highlights

7qaa is a 2 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.76Å
Ligands:	,
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]

Publication Abstract from PubMed

Retinoid X receptors (RXRalpha, beta, and gamma) are essential members of the nuclear receptor (NR) superfamily of ligand-dependent transcriptional regulators that bind DNA response elements and control the expression of large gene networks. As obligate heterodimerization partners of many NRs, RXRs are involved in a variety of pathophysiological processes. However, despite this central role in NR signaling, there is still no consensus regarding the precise biological functions of RXRs and the putative role of the endogenous ligands (rexinoids) previously proposed for these receptors. Based on available crystal structures, we introduced a series of amino acid substitutions into the ligand-binding pocket of all three RXR subtypes in order to alter their binding properties. Subsequent characterization using a battery of cell-based and in vitro assays led to the identification of a double mutation abolishing the binding of any ligand while keeping the other receptor functions intact and a triple mutation that selectively impairs interaction with natural rexinoids but not with some synthetic ligands. We also report crystal structures that help understand the specific ligand-binding capabilities of both variants. These RXR variants, either fully disabled for ligand binding or retaining the property of being activated by synthetic compounds, represent unique tools that could be used in future studies to probe the presence of active endogenous rexinoids in tissues/organs and to investigate their role in vivo. Last, we provide data suggesting a possible involvement of fatty acids in the weak interaction of RXRs with corepressors.

Design and in vitro characterization of RXR variants as tools to investigate the biological role of endogenous rexinoids.,le Maire A, Rey M, Vivat V, Guee L, Blanc P, Malosse C, Chamot-Rooke J, Germain P, Bourguet W J Mol Endocrinol. 2022 Aug 4;69(3):377-390. doi: 10.1530/JME-22-0021. Print 2022 , Oct 1. PMID:35900852^[4]

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
↑ le Maire A, Rey M, Vivat V, Guee L, Blanc P, Malosse C, Chamot-Rooke J, Germain P, Bourguet W. Design and in vitro characterization of RXR variants as tools to investigate the biological role of endogenous rexinoids. J Mol Endocrinol. 2022 Aug 4;69(3):377-390. doi: 10.1530/JME-22-0021. Print 2022 , Oct 1. PMID:35900852 doi:http://dx.doi.org/10.1530/JME-22-0021

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7qaa"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 7qaa is ON HOLD  until sometime in the future
+==Crystal structure of RARalpha/RXRalpha ligand binding domain heterodimer in complex with BMS614 and oleic acid==
+<StructureSection load='7qaa' size='340' side='right'caption='[[7qaa]], [[Resolution|resolution]] 2.76&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[7qaa]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QAA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QAA FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.76&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMS:4-[(4,4-DIMETHYL-1,2,3,4-TETRAHYDRO-[1,2]BINAPTHALENYL-7-CARBONYL)-AMINO]-BENZOIC+ACID'>BMS</scene>, <scene name='pdbligand=OLA:OLEIC+ACID'>OLA</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=7qaa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qaa OCA], [https://pdbe.org/7qaa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qaa RCSB], [https://www.ebi.ac.uk/pdbsum/7qaa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qaa ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/RXRA_MOUSE 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.<ref>PMID:1310259</ref> <ref>PMID:10383391</ref> <ref>PMID:12032153</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Retinoid X receptors (RXRalpha, beta, and gamma) are essential members of the nuclear receptor (NR) superfamily of ligand-dependent transcriptional regulators that bind DNA response elements and control the expression of large gene networks. As obligate heterodimerization partners of many NRs, RXRs are involved in a variety of pathophysiological processes. However, despite this central role in NR signaling, there is still no consensus regarding the precise biological functions of RXRs and the putative role of the endogenous ligands (rexinoids) previously proposed for these receptors. Based on available crystal structures, we introduced a series of amino acid substitutions into the ligand-binding pocket of all three RXR subtypes in order to alter their binding properties. Subsequent characterization using a battery of cell-based and in vitro assays led to the identification of a double mutation abolishing the binding of any ligand while keeping the other receptor functions intact and a triple mutation that selectively impairs interaction with natural rexinoids but not with some synthetic ligands. We also report crystal structures that help understand the specific ligand-binding capabilities of both variants. These RXR variants, either fully disabled for ligand binding or retaining the property of being activated by synthetic compounds, represent unique tools that could be used in future studies to probe the presence of active endogenous rexinoids in tissues/organs and to investigate their role in vivo. Last, we provide data suggesting a possible involvement of fatty acids in the weak interaction of RXRs with corepressors.
-Authors: le Maire, A., Vivat, V., Guee, L., Blanc, P., Malosse, C., Chamot-Rooke, J., Germain, P., Bourguet, w.
+Design and in vitro characterization of RXR variants as tools to investigate the biological role of endogenous rexinoids.,le Maire A, Rey M, Vivat V, Guee L, Blanc P, Malosse C, Chamot-Rooke J, Germain P, Bourguet W J Mol Endocrinol. 2022 Aug 4;69(3):377-390. doi: 10.1530/JME-22-0021. Print 2022 , Oct 1. PMID:35900852<ref>PMID:35900852</ref>
-Description: Crystal structure of RARalpha/RXRalpha ligand binding domain heterodimer in complex with BMS614 and oleic acid
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Germain, P]]
+<div class="pdbe-citations 7qaa" style="background-color:#fffaf0;"></div>
-[[Category: Chamot-Rooke, J]]
-[[Category: Le Maire, A]]
+==See Also==
-[[Category: Vivat, V]]
+*[[Retinoid X receptor 3D structures|Retinoid X receptor 3D structures]]
-[[Category: Malosse, C]]
+== References ==
-[[Category: Blanc, P]]
+<references/>
-[[Category: Guee, L]]
+__TOC__
-[[Category: Bourguet, W]]
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Mus musculus]]
+[[Category: Blanc P]]
+[[Category: Bourguet w]]
+[[Category: Chamot-Rooke J]]
+[[Category: Germain P]]
+[[Category: Guee L]]
+[[Category: Malosse C]]
+[[Category: Vivat V]]
+[[Category: Le Maire A]]

7qaa

From Proteopedia

Current revision

Crystal structure of RARalpha/RXRalpha ligand binding domain heterodimer in complex with BMS614 and oleic acid

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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