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{{STRUCTURE_4iv2|  PDB=4iv2  |  SCENE=  }}
===Crystal Structure of the Estrogen Receptor alpha Ligand-binding Domain in Complex with Dynamic WAY-derivative, 5a===


==Disease==
==Crystal Structure of the Estrogen Receptor alpha Ligand-binding Domain in Complex with Dynamic WAY-derivative, 5a==
[[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.  
<StructureSection load='4iv2' size='340' side='right'caption='[[4iv2]], [[Resolution|resolution]] 2.14&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4iv2]] 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=4IV2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IV2 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.14&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1GR:4-[1-(2-METHYLPROPYL)-7-(TRIFLUOROMETHYL)-1H-INDAZOL-3-YL]BENZENE-1,3-DIOL'>1GR</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4iv2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4iv2 OCA], [https://pdbe.org/4iv2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4iv2 RCSB], [https://www.ebi.ac.uk/pdbsum/4iv2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4iv2 ProSAT]</span></td></tr>
</table>
== Function ==
[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>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Ligand-binding dynamics control allosteric signaling through the estrogen receptor-alpha (ERalpha), but the biological consequences of such dynamic binding orientations are unknown. Here, we compare a set of ER ligands having dynamic binding orientation (dynamic ligands) with a control set of isomers that are constrained to bind in a single orientation (constrained ligands). Proliferation of breast cancer cells directed by constrained ligands is associated with DNA binding, coactivator recruitment and activation of the estrogen-induced gene GREB1, reflecting a highly interconnected signaling network. In contrast, proliferation driven by dynamic ligands is associated with induction of ERalpha-mediated transcription in a DNA-binding domain (DBD)-dependent manner. Further, dynamic ligands showed enhanced anti-inflammatory activity. The DBD-dependent profile was predictive of these signaling patterns in a larger diverse set of natural and synthetic ligands. Thus, ligand dynamics directs unique signaling pathways and reveals a new role of the DBD in allosteric control of ERalpha-mediated signaling.


==Function==
Ligand-binding dynamics rewire cellular signaling via estrogen receptor-alpha.,Srinivasan S, Nwachukwu JC, Parent AA, Cavett V, Nowak J, Hughes TS, Kojetin DJ, Katzenellenbogen JA, Nettles KW Nat Chem Biol. 2013 May;9(5):326-32. doi: 10.1038/nchembio.1214. Epub 2013 Mar, 24. PMID:23524984<ref>PMID:23524984</ref>
[[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>  


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[4iv2]] 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=4IV2 OCA].
</div>
<div class="pdbe-citations 4iv2" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
<references group="xtra"/><references/>
*[[Estrogen receptor 3D structures|Estrogen receptor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Cavett, V.]]
[[Category: Large Structures]]
[[Category: Hughes, T S.]]
[[Category: Cavett V]]
[[Category: Katzenellenbogen, J A.]]
[[Category: Hughes TS]]
[[Category: Kojetin, D J.]]
[[Category: Katzenellenbogen JA]]
[[Category: Nettles, K W.]]
[[Category: Kojetin DJ]]
[[Category: Nowak, J.]]
[[Category: Nettles KW]]
[[Category: Nwachukwu, J C.]]
[[Category: Nowak J]]
[[Category: Parent, A A.]]
[[Category: Nwachukwu JC]]
[[Category: Srinivasan, S.]]
[[Category: Parent AA]]
[[Category: Ligand-binding]]
[[Category: Srinivasan S]]
[[Category: Nuclear hormone receptor]]
[[Category: Nucleus]]
[[Category: Transcription]]
[[Category: Transcription factor]]

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