1rdt

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{{STRUCTURE_1rdt| PDB=1rdt | SCENE= }}
 
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===Crystal Structure of a new rexinoid bound to the RXRalpha ligand binding doamin in the RXRalpha/PPARgamma heterodimer===
 
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{{ABSTRACT_PUBMED_15056000}}
 
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==Function==
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==Crystal Structure of a new rexinoid bound to the RXRalpha ligand binding doamin in the RXRalpha/PPARgamma heterodimer==
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[[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> [[http://www.uniprot.org/uniprot/PPAT_HUMAN PPAT_HUMAN]] Dephosphorylates receptor tyrosine-protein kinase erbB-4 and inhibits the ligand-induced proteolytic cleavage.<ref>PMID:15219672</ref>
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<StructureSection load='1rdt' size='340' side='right'caption='[[1rdt]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1rdt]] 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=1RDT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1RDT 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]] 2.4&#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=570:2-(2-BENZOYL-PHENYLAMINO)-3-{4-[2-(5-METHYL-2-PHENYL-OXAZOL-4-YL)-ETHOXY]-PHENYL}-PROPIONIC+ACID'>570</scene>, <scene name='pdbligand=L79:(S)-(2E)-3[4-(5,5,8,8-TETRAMETHYL-5,6,7,8-TETRAHYDRO-2-NAPHTHALENYL)TETRAHYDRO-1-BENZOFURAN-2-YL]-2-PROPENOIC+ACID'>L79</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=1rdt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1rdt OCA], [https://pdbe.org/1rdt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1rdt RCSB], [https://www.ebi.ac.uk/pdbsum/1rdt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1rdt 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/rd/1rdt_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=1rdt 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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A series of tetrahydrobenzofuranyl and tetrahydrobenzothienyl propenoic acids that showed potent agonist activity against RXRalpha were synthesized via a structure-based design approach. Among the compounds studied, 46a,b showed not only very good potency against RXRalpha (K(i) = 6 nM) but was also found to be greater than 167-fold selective vs RARalpha (K(i) &gt; 1000 nM). This compound profiled out as a full agonist in a cell-based transient transfection assay (EC(50) = 3 nM). The two antipodes were separated via chiral chromatography, and 46b was found to be 40-fold more potent than 46a. Interestingly, cocrystallization of 46a,b with the RXRalpha protein generated a liganded structure whereby the (S)-antipode was found in the binding pocket. Given orally in db/db mice or ZDF rats, 46a,b showed a significant glucose-lowering effect and an increase in liver mass. Triglycerides decreased significantly in db/db mice but increased in the ZDF rats. A dose-dependent decrease of nonesterified free fatty acids was seen in ZDF rats but not in db/db mice. These differences indicate a species specific effect of RXR agonists on lipid metabolism.
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==About this Structure==
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Structure-based design of potent retinoid X receptor alpha agonists.,Haffner CD, Lenhard JM, Miller AB, McDougald DL, Dwornik K, Ittoop OR, Gampe RT Jr, Xu HE, Blanchard S, Montana VG, Consler TG, Bledsoe RK, Ayscue A, Croom D J Med Chem. 2004 Apr 8;47(8):2010-29. PMID:15056000<ref>PMID:15056000</ref>
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[[1rdt]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1RDT OCA].
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==See Also==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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*[[Peroxisome Proliferator-Activated Receptors|Peroxisome Proliferator-Activated Receptors]]
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</div>
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*[[Retinoid X receptor|Retinoid X receptor]]
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<div class="pdbe-citations 1rdt" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:015056000</ref><references group="xtra"/><references/>
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*[[Peroxisome proliferator-activated receptor 3D structures|Peroxisome proliferator-activated receptor 3D structures]]
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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>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Blanchard, S.]]
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[[Category: Large Structures]]
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[[Category: Dwornik, K.]]
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[[Category: Blanchard S]]
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[[Category: Gampe, R T.]]
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[[Category: Dwornik K]]
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[[Category: Haffner, C D.]]
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[[Category: Gampe Jr RT]]
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[[Category: Ittoop, O R.]]
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[[Category: Haffner CD]]
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[[Category: Lenhard, J M.]]
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[[Category: Ittoop OR]]
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[[Category: McDougald, D L.]]
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[[Category: Lenhard JM]]
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[[Category: Miller, A B.]]
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[[Category: McDougald DL]]
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[[Category: Montana, V G.]]
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[[Category: Miller AB]]
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[[Category: Xu, H E.]]
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[[Category: Montana VG]]
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[[Category: Hormone]]
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[[Category: Xu HE]]
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[[Category: Hormone-growth factor complex]]
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[[Category: Receptor]]
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Current revision

Crystal Structure of a new rexinoid bound to the RXRalpha ligand binding doamin in the RXRalpha/PPARgamma heterodimer

PDB ID 1rdt

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