3r5m

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Current revision (12:11, 14 March 2024) (edit) (undo)
 
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<StructureSection load='3r5m' size='340' side='right'caption='[[3r5m]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
<StructureSection load='3r5m' size='340' side='right'caption='[[3r5m]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3r5m]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3R5M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3R5M FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3r5m]] 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=3R5M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3R5M FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MLO:5,5-DI(PROP-2-EN-1-YL)BIPHENYL-2,2-DIOL'>MLO</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]] 2.8&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3r5n|3r5n]]</div></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=MLO:5,5-DI(PROP-2-EN-1-YL)BIPHENYL-2,2-DIOL'>MLO</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RXRA, NR2B1 ([https://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=3r5m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3r5m OCA], [https://pdbe.org/3r5m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3r5m RCSB], [https://www.ebi.ac.uk/pdbsum/3r5m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3r5m ProSAT]</span></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=3r5m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3r5m OCA], [https://pdbe.org/3r5m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3r5m RCSB], [https://www.ebi.ac.uk/pdbsum/3r5m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3r5m ProSAT]</span></td></tr>
</table>
</table>
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== Disease ==
 
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[[https://www.uniprot.org/uniprot/NCOA2_HUMAN NCOA2_HUMAN]] Note=Chromosomal aberrations involving NCOA2 may be a cause of acute myeloid leukemias. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation.
 
== Function ==
== Function ==
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[[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> [[https://www.uniprot.org/uniprot/NCOA2_HUMAN NCOA2_HUMAN]] Transcriptional coactivator for steroid receptors and nuclear receptors. Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1). Required with NCOA1 to control energy balance between white and brown adipose tissues.<ref>PMID:9430642</ref>
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Nuclear receptors retinoic X receptor alpha (RXRalpha) and peroxisome proliferator activated receptor gamma (PPARgamma) function potently in metabolic diseases, and are both important targets for anti-diabetic drugs. Coactivation of RXRalpha and PPARgamma is believed to synergize their effects on glucose and lipid metabolism. Here we identify the natural product magnolol as a dual agonist targeting both RXRalpha and PPARgamma. Magnolol was previously reported to enhance adipocyte differentiation and glucose uptake, ameliorate blood glucose level and prevent development of diabetic nephropathy. Although magnolol can bind and activate both of these two nuclear receptors, the transactivation assays indicate that magnolol exhibits biased agonism on the transcription of PPAR-response element (PPRE) mediated by RXRalpha:PPARgamma heterodimer, instead of RXR-response element (RXRE) mediated by RXRalpha:RXRalpha homodimer. To further elucidate the molecular basis for magnolol agonism, we determine both the co-crystal structures of RXRalpha and PPARgamma ligand-binding domains (LBDs) with magnolol. Structural analyses reveal that magnolol adopts its two 5-allyl-2-hydroxyphenyl moieties occupying the acidic and hydrophobic cavities of RXRalpha L-shaped ligand-binding pocket, respectively. While, two magnolol molecules cooperatively accommodate into PPARgamma Y-shaped ligand-binding pocket. Based on these two complex structures, the key interactions for magnolol activating RXRalpha and PPARgamma are determined. As the first report on the dual agonist targeting RXRalpha and PPARgamma with receptor-ligand complex structures, our results are thus expected to help inspect the potential pharmacological mechanism for magnolol functions, and supply useful hits for nuclear receptor multi-target ligand design.
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Molecular determinants of magnolol targeting both RXRalpha and PPARgamma.,Zhang H, Xu X, Chen L, Chen J, Hu L, Jiang H, Shen X PLoS One. 2011;6(11):e28253. Epub 2011 Nov 29. PMID:22140563<ref>PMID:22140563</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 3r5m" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Chen, J]]
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[[Category: Chen J]]
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[[Category: Chen, L]]
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[[Category: Chen L]]
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[[Category: Hu, L]]
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[[Category: Hu L]]
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[[Category: Jiang, H]]
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[[Category: Jiang H]]
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[[Category: Shen, X]]
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[[Category: Shen X]]
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[[Category: Zhang, H]]
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[[Category: Zhang H]]
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[[Category: Nuclear receptor]]
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[[Category: Transcription factor]]
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[[Category: Transcription-transcription agonist complex]]
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Current revision

Crystal structure of RXRalphaLBD complexed with the agonist magnolol

PDB ID 3r5m

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Proteopedia Page Contributors and Editors (what is this?)

OCA

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