6a60

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==Crystal structure of human FXR/RXR-LBD heterodimer bound to GW4064 and 9cRA and SRC1==
==Crystal structure of human FXR/RXR-LBD heterodimer bound to GW4064 and 9cRA and SRC1==
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<StructureSection load='6a60' size='340' side='right' caption='[[6a60]], [[Resolution|resolution]] 3.05&Aring;' scene=''>
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<StructureSection load='6a60' size='340' side='right'caption='[[6a60]], [[Resolution|resolution]] 3.05&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6a60]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6A60 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6A60 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6a60]] 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=6A60 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6A60 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=064:3-[(E)-2-(2-CHLORO-4-{[3-(2,6-DICHLOROPHENYL)-5-(1-METHYLETHYL)ISOXAZOL-4-YL]METHOXY}PHENYL)ETHENYL]BENZOIC+ACID'>064</scene>, <scene name='pdbligand=9CR:(9CIS)-RETINOIC+ACID'>9CR</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.05&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6a5w|6a5w]], [[6a5x|6a5x]], [[6a5y|6a5y]], [[6a5z|6a5z]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=064:3-[(E)-2-(2-CHLORO-4-{[3-(2,6-DICHLOROPHENYL)-5-(1-METHYLETHYL)ISOXAZOL-4-YL]METHOXY}PHENYL)ETHENYL]BENZOIC+ACID'>064</scene>, <scene name='pdbligand=9CR:(9CIS)-RETINOIC+ACID'>9CR</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NR1H4, BAR, FXR, HRR1, RIP14 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), RXRA, NR2B1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6a60 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6a60 OCA], [https://pdbe.org/6a60 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6a60 RCSB], [https://www.ebi.ac.uk/pdbsum/6a60 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6a60 ProSAT]</span></td></tr>
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<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=6a60 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6a60 OCA], [http://pdbe.org/6a60 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6a60 RCSB], [http://www.ebi.ac.uk/pdbsum/6a60 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6a60 ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/NR1H4_HUMAN NR1H4_HUMAN]] Ligand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1) through the induction of NR0B2 or FGF19 expression, via two distinct mechanisms. Activates the intestinal bile acid-binding protein (IBABP). Activates the transcription of bile salt export pump ABCB11 by directly recruiting histone methyltransferase CARM1 to this locus.<ref>PMID:10334992</ref> <ref>PMID:10334993</ref> <ref>PMID:12815072</ref> <ref>PMID:15471871</ref> <ref>PMID:12718892</ref> <ref>PMID:18621523</ref> <ref>PMID:19410460</ref> <ref>PMID:19586769</ref> [[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>
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[https://www.uniprot.org/uniprot/NR1H4_HUMAN NR1H4_HUMAN] Ligand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1) through the induction of NR0B2 or FGF19 expression, via two distinct mechanisms. Activates the intestinal bile acid-binding protein (IBABP). Activates the transcription of bile salt export pump ABCB11 by directly recruiting histone methyltransferase CARM1 to this locus.<ref>PMID:10334992</ref> <ref>PMID:10334993</ref> <ref>PMID:12815072</ref> <ref>PMID:15471871</ref> <ref>PMID:12718892</ref> <ref>PMID:18621523</ref> <ref>PMID:19410460</ref> <ref>PMID:19586769</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Nuclear receptor farnesoid X receptor (FXR) functions as the major bile acid (BA) sensor coordinating cholesterol metabolism, lipid homeostasis and absorption of dietary fats and vitamins. Because of its central role in metabolism, FXR represents an important drug target to manage metabolic and other diseases, such as primary biliary cirrhosis and non-alcoholic steatohepatitis. FXR and nuclear receptor retinoid X receptor alpha (RXRalpha) form a heterodimer that controls the expression of numerous downstream genes. To date, the structural basis and functional consequences of the FXR/RXR heterodimer interaction have remained unclear. Herein, we present the crystal structures of the heterodimeric complex formed between the ligand-binding domains of human FXR and RXRalpha. We show that both FXR and RXR bind to the transcriptional coregulator steroid receptor coactivator 1 (SRC1) with higher affinity when they are part of the heterodimer complex than when they are in their respective monomeric states. Furthermore, structural comparisons of the FXR/RXRalpha heterodimers and the FXR monomers bound with different ligands indicated that both heterodimerization and ligand binding induce a conformational change in the C terminus of helix 11 in FXR that affects the stability of the coactivator binding surface and the coactivator binding in FXR. In summary, our findings shed light on the allosteric signal transduction in the FXR/RXR heterodimer, which may be utilized for future drug development targeting FXR.
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Ligand binding and heterodimerization with retinoid X receptor alpha (RXRalpha) induce farnesoid X receptor (FXR) conformational changes affecting co-activator binding.,Wang N, Zou Q, Xu J, Zhang J, Liu J J Biol Chem. 2018 Oct 1. pii: RA118.004652. doi: 10.1074/jbc.RA118.004652. PMID:30275017<ref>PMID:30275017</ref>
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==See Also==
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*[[Bile acid receptor 3D structures|Bile acid receptor 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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*[[Retinoid X receptor 3D structures|Retinoid X receptor 3D structures]]
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</div>
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<div class="pdbe-citations 6a60" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Liu, J]]
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[[Category: Large Structures]]
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[[Category: Wang, N]]
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[[Category: Liu J]]
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[[Category: Nuclear receptor heterodimer]]
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[[Category: Wang N]]
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[[Category: Transcription]]
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Current revision

Crystal structure of human FXR/RXR-LBD heterodimer bound to GW4064 and 9cRA and SRC1

PDB ID 6a60

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