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The | ==Crystal Structure of the ER-alpha Ligand-binding Domain (Y537S) in Complex with 2,5-bis(2-fluoro-4-hydroxyphenyl)thiophene 1-oxide== | ||
<StructureSection load='5tm1' size='340' side='right' caption='[[5tm1]], [[Resolution|resolution]] 2.23Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5tm1]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TM1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TM1 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7EQ:2,5-BIS(2-FLUORO-4-HYDROXYPHENYL)-1H-1LAMBDA~4~-THIOPHEN-1-ONE'>7EQ</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5kr9|5kr9]], [[5kra|5kra]], [[5krc|5krc]], [[5krf|5krf]], [[5krh|5krh]], [[5kri|5kri]], [[5krj|5krj]], [[5krk|5krk]], [[5krl|5krl]], [[5krm|5krm]], [[5krn|5krn]], [[5kro|5kro]], [[5tld|5tld]], [[5tlf|5tlf]], [[5tlg|5tlg]], [[5tll|5tll]], [[5tlm|5tlm]], [[5tlo|5tlo]], [[5tlp|5tlp]], [[5tm4|5tm4]], [[5tm5|5tm5]], [[5tm6|5tm6]], [[5tm7|5tm7]], [[5tm8|5tm8]], [[5tm9|5tm9]], [[5tlt|5tlt]], [[5tlu|5tlu]], [[5tlv|5tlv]], [[5tlx|5tlx]], [[5tly|5tly]], [[5tm2|5tm2]], [[5tm3|5tm3]], [[5tml|5tml]], [[5tmm|5tmm]], [[5tmo|5tmo]], [[5tmq|5tmq]], [[5tmr|5tmr]], [[5tms|5tms]], [[5tmt|5tmt]], [[5tmu|5tmu]], [[5tmv|5tmv]], [[5tmw|5tmw]], [[5tmz|5tmz]], [[5tn1|5tn1]], [[5tn3|5tn3]], [[5tn4|5tn4]], [[5tn5|5tn5]], [[5tn6|5tn6]], [[5tn7|5tn7]], [[5tn8|5tn8]]</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5tm1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tm1 OCA], [http://pdbe.org/5tm1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tm1 RCSB], [http://www.ebi.ac.uk/pdbsum/5tm1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tm1 ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[http://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 == | |||
[[http://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> [[http://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> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Environmental estrogens and anti-hormone therapies for breast cancer have diverse tissue- and signaling-pathway-selective outcomes, but how estrogen receptor alpha (ERalpha) mediates this phenotypic diversity is poorly understood. We implemented a statistical approach to allow unbiased, parallel analyses of multiple crystal structures, and identified subtle perturbations of ERalpha structure by different synthetic and environmental estrogens. Many of these perturbations were in the sub-A range, within the noise of the individual structures, but contributed significantly to the activities of synthetic and environmental estrogens. Combining structural perturbation data from many structures with quantitative cellular activity profiles of the ligands enabled identification of structural rules for ligand-specific allosteric signaling-predicting activity from structure. This approach provides a framework for understanding the diverse effects of environmental estrogens and for guiding iterative medicinal chemistry efforts to generate improved breast cancer therapies, an approach that can be applied to understanding other ligand-regulated allosteric signaling pathways. | |||
Systems Structural Biology Analysis of Ligand Effects on ERalpha Predicts Cellular Response to Environmental Estrogens and Anti-hormone Therapies.,Nwachukwu JC, Srinivasan S, Bruno NE, Nowak J, Wright NJ, Minutolo F, Rangarajan ES, Izard T, Yao XQ, Grant BJ, Kojetin DJ, Elemento O, Katzenellenbogen JA, Nettles KW Cell Chem Biol. 2016 Dec 21. pii: S2451-9456(16)30437-8. doi:, 10.1016/j.chembiol.2016.11.014. PMID:28042045<ref>PMID:28042045</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5tm1" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Bruno, N E]] | |||
[[Category: Elemento, O]] | |||
[[Category: Katzenellenbogen, J A]] | |||
[[Category: Kojetin, D J]] | |||
[[Category: Nettles, K W]] | |||
[[Category: Nowak, J]] | |||
[[Category: Nwachukwu, J C]] | |||
[[Category: Srinivasan, S]] | [[Category: Srinivasan, S]] | ||
[[Category: Wright, N | [[Category: Wright, N J]] | ||
[[Category: | [[Category: Ligand binding]] | ||
[[Category: | [[Category: Nuclear receptor]] | ||
[[Category: | [[Category: Protein-ligand complex]] | ||
[[Category: | [[Category: Transcription]] | ||
[[Category: Transcription factor]] | |||