1xqc

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{{Seed}}
 
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[[Image:1xqc.png|left|200px]]
 
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==X-ray structure of ERalpha LBD bound to a tetrahydroisoquinoline SERM ligand at 2.05A resolution==
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The line below this paragraph, containing "STRUCTURE_1xqc", creates the "Structure Box" on the page.
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<StructureSection load='1xqc' size='340' side='right'caption='[[1xqc]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[1xqc]] 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=1XQC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1XQC FirstGlance]. <br>
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or leave the SCENE parameter empty for the default display.
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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]] 2.05&#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=AEJ:(1S)-1-{4-[(9AR)-OCTAHYDRO-2H-PYRIDO[1,2-A]PYRAZIN-2-YL]PHENYL}-2-PHENYL-1,2,3,4-TETRAHYDROISOQUINOLIN-6-OL'>AEJ</scene></td></tr>
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{{STRUCTURE_1xqc| PDB=1xqc | SCENE= }}
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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=1xqc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xqc OCA], [https://pdbe.org/1xqc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1xqc RCSB], [https://www.ebi.ac.uk/pdbsum/1xqc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1xqc ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/ESR1_HUMAN ESR1_HUMAN] Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Isoform 3 can bind to ERE and inhibit isoform 1.<ref>PMID:7651415</ref> <ref>PMID:10970861</ref> <ref>PMID:9328340</ref> <ref>PMID:10681512</ref> <ref>PMID:10816575</ref> <ref>PMID:11477071</ref> <ref>PMID:11682626</ref> <ref>PMID:15078875</ref> <ref>PMID:16043358</ref> <ref>PMID:15891768</ref> <ref>PMID:16684779</ref> <ref>PMID:18247370</ref> <ref>PMID:17932106</ref> <ref>PMID:19350539</ref> <ref>PMID:20705611</ref> <ref>PMID:21937726</ref> <ref>PMID:21330404</ref> <ref>PMID:22083956</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/xq/1xqc_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=1xqc 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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We disclose herein the discovery of estrogen receptor alpha (ERalpha) selective estrogen receptor modulators (SERMs) of the tetrahydroisoquinoline series that incorporate novel conformationally restricted side chains as replacement of the aminoethoxy residue typical of SERMs. Molecular modeling studies used in conjunction with the X-ray crystal structure of the ERalpha ligand binding domain (LBD) with raloxifene (7) suggested a diazadecaline moiety as a viable mimic of the SERM side chain. On the basis of this knowledge, the piperidinylethoxy moiety of our lead compound 60 was replaced by a diazadecaline subunit, providing the novel tetrahydroisoquinoline 29. In addition to exhibiting a binding affinity to ERalpha and antagonistic properties in the estrogen response element and MCF-7 assays similar to those of the parent compound 60, ligand 29 showed a reduced agonist behavior in the MCF-7 assay in the absence of 17beta-estradiol. These data point toward the fact that 29 may have a potential for breast cancer prevention/treatment in vivo, a feature which is particularly attractive in the quest for safe alternatives to hormone replacement therapy. In a pharmacokinetic experiment carried out in rats, 29 displayed an interesting profile, with a bioavailability of 49%. We also disclose the X-ray crystal structure of 29 in complex with ERalpha-LBD, which reveals the preferred configurations of 29 at the two chiral centers and the details of its interactions with the receptor. Finally, our structure-activity relationship studies show that other analogues bearing constrained side chains retain potency and antagonist activity and that a 3-OH substituted phenyl D-ring increases the selectivity of a set of piperazinyl-containing ligands in favor of ERalpha over ERbeta.
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===X-ray structure of ERalpha LBD bound to a tetrahydroisoquinoline SERM ligand at 2.05A resolution===
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Selective estrogen receptor modulators with conformationally restricted side chains. Synthesis and structure-activity relationship of ERalpha-selective tetrahydroisoquinoline ligands.,Renaud J, Bischoff SF, Buhl T, Floersheim P, Fournier B, Geiser M, Halleux C, Kallen J, Keller H, Ramage P J Med Chem. 2005 Jan 27;48(2):364-79. PMID:15658851<ref>PMID:15658851</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 1xqc" style="background-color:#fffaf0;"></div>
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==See Also==
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The line below this paragraph, {{ABSTRACT_PUBMED_15658851}}, adds the Publication Abstract to the page
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*[[Estrogen receptor 3D structures|Estrogen receptor 3D structures]]
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(as it appears on PubMed at http://www.pubmed.gov), where 15658851 is the PubMed ID number.
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== References ==
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<references/>
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{{ABSTRACT_PUBMED_15658851}}
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__TOC__
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</StructureSection>
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==About this Structure==
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1XQC is a 4 chains structure of sequences 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=1XQC OCA].
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==Reference==
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<ref group="xtra">PMID:15658851</ref><references group="xtra"/>
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Bischoff, S F.]]
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[[Category: Large Structures]]
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[[Category: Buhl, T.]]
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[[Category: Bischoff SF]]
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[[Category: Floersheim, P.]]
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[[Category: Buhl T]]
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[[Category: Fournier, B.]]
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[[Category: Floersheim P]]
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[[Category: Geiser, M.]]
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[[Category: Fournier B]]
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[[Category: Halleux, C.]]
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[[Category: Geiser M]]
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[[Category: Kallen, J.]]
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[[Category: Halleux C]]
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[[Category: Keller, H J.]]
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[[Category: Kallen J]]
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[[Category: Ramage, P.]]
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[[Category: Keller HJ]]
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[[Category: Renaud, J.]]
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[[Category: Ramage P]]
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[[Category: Alpha-helical sandwich]]
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[[Category: Renaud J]]
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[[Category: Ligand binding domain]]
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[[Category: Nuclear hormone receptor]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Feb 16 21:23:59 2009''
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Current revision

X-ray structure of ERalpha LBD bound to a tetrahydroisoquinoline SERM ligand at 2.05A resolution

PDB ID 1xqc

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