2qe4

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[[Image:2qe4.jpg|left|200px]]<br /><applet load="2qe4" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="2qe4, resolution 2.40&Aring;" />
 
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'''Estrogen receptor alpha ligand-binding domain in complex with a benzopyran agonist'''<br />
 
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==Overview==
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==Estrogen receptor alpha ligand-binding domain in complex with a benzopyran agonist==
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Benzopyrans are selective estrogen receptor (ER) beta agonists (SERBAs), which bind the ER receptor subtypes alpha and beta in opposite, orientations. We have used structure based drug design to show that this, unique phenomena can be exploited via substitution at the 8-position of, the benzopyran A-ring to disrupt binding to ERalpha, thus improving ERbeta, subtype selectivity. X-ray cocrystal structures with ERalpha and ERbeta, are supportive of this approach to improve selectivity in this structural, class.
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<StructureSection load='2qe4' size='340' side='right'caption='[[2qe4]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2qe4]] 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=2QE4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2QE4 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=JJ3:(3AS,4R,9BR)-4-(4-HYDROXYPHENYL)-6-(METHOXYMETHYL)-1,2,3,3A,4,9B-HEXAHYDROCYCLOPENTA[C]CHROMEN-8-OL'>JJ3</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=2qe4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qe4 OCA], [https://pdbe.org/2qe4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2qe4 RCSB], [https://www.ebi.ac.uk/pdbsum/2qe4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2qe4 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/qe/2qe4_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=2qe4 ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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2QE4 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=JJ3:'>JJ3</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QE4 OCA].
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*[[Estrogen receptor 3D structures|Estrogen receptor 3D structures]]
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== References ==
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==Reference==
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<references/>
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Benzopyrans as selective estrogen receptor beta agonists (SERBAs). Part 4: Functionalization of the benzopyran A-ring., Norman BH, Richardson TI, Dodge JA, Pfeifer LA, Durst GL, Wang Y, Durbin JD, Krishnan V, Dinn SR, Liu S, Reilly JE, Ryter KT, Bioorg Med Chem Lett. 2007 Jul 13;. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17662603 17662603]
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Dinn, S.R.]]
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[[Category: Dinn SR]]
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[[Category: Dodge, J.A.]]
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[[Category: Dodge JA]]
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[[Category: Durbin, J.D.]]
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[[Category: Durbin JD]]
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[[Category: Durst, G.L.]]
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[[Category: Durst GL]]
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[[Category: Krishnan, V.]]
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[[Category: Krishnan V]]
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[[Category: Liu, S.Q.]]
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[[Category: Liu SQ]]
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[[Category: Norman, B.H.]]
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[[Category: Norman BH]]
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[[Category: Pfeifer, L.A.]]
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[[Category: Pfeifer LA]]
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[[Category: Reilly, J.E.]]
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[[Category: Reilly JE]]
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[[Category: Richardson, T.I.]]
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[[Category: Richardson TI]]
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[[Category: Ryter, K.T.]]
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[[Category: Ryter KT]]
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[[Category: Wang, Y.]]
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[[Category: Wang Y]]
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[[Category: JJ3]]
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[[Category: alternative splicing]]
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[[Category: dna-binding]]
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[[Category: ligand-binding domain]]
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[[Category: lipid-binding]]
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[[Category: metal-binding]]
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[[Category: nuclear protein]]
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[[Category: nuclear receptor]]
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[[Category: phosphorylation]]
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[[Category: polymorphism]]
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[[Category: steroid-binding]]
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[[Category: transcription]]
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[[Category: transcription regulation]]
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[[Category: zinc]]
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[[Category: zinc-finger]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 13:46:30 2008''
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Current revision

Estrogen receptor alpha ligand-binding domain in complex with a benzopyran agonist

PDB ID 2qe4

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