1mv9

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(New page: 200px<br /> <applet load="1mv9" size="450" color="white" frame="true" align="right" spinBox="true" caption="1mv9, resolution 1.9&Aring;" /> '''Crystal Structure of...)
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[[Image:1mv9.gif|left|200px]]<br />
 
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<applet load="1mv9" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1mv9, resolution 1.9&Aring;" />
 
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'''Crystal Structure of the human RXR alpha ligand binding domain bound to the eicosanoid DHA (Docosa Hexaenoic Acid) and a coactivator peptide'''<br />
 
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==Overview==
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==Crystal Structure of the human RXR alpha ligand binding domain bound to the eicosanoid DHA (Docosa Hexaenoic Acid) and a coactivator peptide==
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The nuclear receptor RXR is an obligate partner in many signal, transduction pathways. We report the high-resolution structures of two, complexes of the human RXRalpha ligand-binding domain specifically bound, to two different and chemically unrelated agonist compounds: docosa, hexaenoic acid, a natural derivative of eicosanoic acid, present in, mammalian cells and recently identified as a potential endogenous RXR, ligand in the mouse brain, and the synthetic ligand BMS 649. In both, structures the RXR-ligand-binding domain forms homodimers and exhibits the, active conformation previously observed with 9-cis-RA. Analysis of the, differences in ligand-protein contacts (predominantly van der Waals, forces) and binding cavity geometries and volumes for the several, agonist-bound RXR structures clarifies the structural features important, for ligand recognition. The L-shaped ligand-binding pocket adapts to the, diverse ligands, especially at the level of residue N306, which might thus, constitute a new target for drug-design. Despite its highest affinity, 9-cis-RA displays the lowest number of ligand-protein contacts. These, structural results support the idea that docosa hexaenoic acid and related, fatty acids could be natural agonists of RXRs and question the real nature, of the endogenous ligand(s) in mammalian cells.
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<StructureSection load='1mv9' size='340' side='right'caption='[[1mv9]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1mv9]] is a 2 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=1MV9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1MV9 FirstGlance]. <br>
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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]] 1.9&#8491;</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=HXA:DOCOSA-4,7,10,13,16,19-HEXAENOIC+ACID'>HXA</scene></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=1mv9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1mv9 OCA], [https://pdbe.org/1mv9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1mv9 RCSB], [https://www.ebi.ac.uk/pdbsum/1mv9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1mv9 ProSAT]</span></td></tr>
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</table>
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== 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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/mv/1mv9_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1mv9 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The nuclear receptor RXR is an obligate partner in many signal transduction pathways. We report the high-resolution structures of two complexes of the human RXRalpha ligand-binding domain specifically bound to two different and chemically unrelated agonist compounds: docosa hexaenoic acid, a natural derivative of eicosanoic acid, present in mammalian cells and recently identified as a potential endogenous RXR ligand in the mouse brain, and the synthetic ligand BMS 649. In both structures the RXR-ligand-binding domain forms homodimers and exhibits the active conformation previously observed with 9-cis-RA. Analysis of the differences in ligand-protein contacts (predominantly van der Waals forces) and binding cavity geometries and volumes for the several agonist-bound RXR structures clarifies the structural features important for ligand recognition. The L-shaped ligand-binding pocket adapts to the diverse ligands, especially at the level of residue N306, which might thus constitute a new target for drug-design. Despite its highest affinity 9-cis-RA displays the lowest number of ligand-protein contacts. These structural results support the idea that docosa hexaenoic acid and related fatty acids could be natural agonists of RXRs and question the real nature of the endogenous ligand(s) in mammalian cells.
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==About this Structure==
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Molecular recognition of agonist ligands by RXRs.,Egea PF, Mitschler A, Moras D Mol Endocrinol. 2002 May;16(5):987-97. PMID:11981034<ref>PMID:11981034</ref>
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1MV9 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with HXA as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1MV9 OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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Molecular recognition of agonist ligands by RXRs., Egea PF, Mitschler A, Moras D, Mol Endocrinol. 2002 May;16(5):987-97. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11981034 11981034]
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</div>
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[[Category: Homo sapiens]]
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<div class="pdbe-citations 1mv9" style="background-color:#fffaf0;"></div>
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[[Category: Protein complex]]
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[[Category: Egea, P.F.]]
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[[Category: Mitschler, A.]]
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[[Category: Moras, D.]]
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[[Category: HXA]]
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[[Category: nuclear protein]]
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[[Category: transcription regulation]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:15:19 2007''
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==See Also==
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*[[Retinoid X receptor 3D structures|Retinoid X receptor 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Egea PF]]
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[[Category: Mitschler A]]
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[[Category: Moras D]]

Current revision

Crystal Structure of the human RXR alpha ligand binding domain bound to the eicosanoid DHA (Docosa Hexaenoic Acid) and a coactivator peptide

PDB ID 1mv9

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