5u2d
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal Structure of the ER-alpha Ligand-binding Domain (Y537S) in complex with Oxabicyclic Heptene Sulfonate (OBHS)== | |
| + | <StructureSection load='5u2d' size='340' side='right' caption='[[5u2d]], [[Resolution|resolution]] 1.86Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5u2d]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5U2D OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5U2D FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=OBH:CYCLOHEXA-2,5-DIEN-1-YL+(1S,2R,4S)-5,6-BIS(4-HYDROXYPHENYL)-7-OXABICYCLO[2.2.1]HEPT-5-ENE-2-SULFONATE'>OBH</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5u2b|5u2b]]</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=5u2d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u2d OCA], [http://pdbe.org/5u2d PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5u2d RCSB], [http://www.ebi.ac.uk/pdbsum/5u2d PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5u2d 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 == | ||
| + | Human breast cancers that exhibit high proportions of immune cells and elevated levels of pro-inflammatory cytokines predict poor prognosis. Here, we demonstrate that treatment of human MCF-7 breast cancer cells with pro-inflammatory cytokines results in ERalpha-dependent activation of gene expression and proliferation, in the absence of ligand or presence of 4OH-tamoxifen (TOT). Cytokine activation of ERalpha and endocrine resistance is dependent on phosphorylation of ERalpha at S305 in the hinge domain. Phosphorylation of S305 by IKKbeta establishes an ERalpha cistrome that substantially overlaps with the estradiol (E2)-dependent ERalpha cistrome. Structural analyses suggest that S305-P forms a charge-linked bridge with the C-terminal F domain of ERalpha that enables inter-domain communication and constitutive activity from the N-terminal coactivator-binding site, revealing the structural basis of endocrine resistance. ERalpha therefore functions as a transcriptional effector of cytokine-induced IKKbeta signaling, suggesting a mechanism through which the tumor microenvironment controls tumor progression and endocrine resistance. | ||
| - | + | Structural and Molecular Mechanisms of Cytokine-Mediated Endocrine Resistance in Human Breast Cancer Cells.,Stender JD, Nwachukwu JC, Kastrati I, Kim Y, Strid T, Yakir M, Srinivasan S, Nowak J, Izard T, Rangarajan ES, Carlson KE, Katzenellenbogen JA, Yao XQ, Grant BJ, Leong HS, Lin CY, Frasor J, Nettles KW, Glass CK Mol Cell. 2017 Mar 16;65(6):1122-1135.e5. doi: 10.1016/j.molcel.2017.02.008. PMID:28306507<ref>PMID:28306507</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | <div class="pdbe-citations 5u2d" style="background-color:#fffaf0;"></div> | |
| - | + | == References == | |
| - | + | <references/> | |
| - | + | __TOC__ | |
| - | [[Category: Carlson, K | + | </StructureSection> |
| + | [[Category: Carlson, K E]] | ||
[[Category: Erumbi, R]] | [[Category: Erumbi, R]] | ||
[[Category: Izard, T]] | [[Category: Izard, T]] | ||
| + | [[Category: Katzenellenbogen, J A]] | ||
| + | [[Category: Nettles, K W]] | ||
| + | [[Category: Nowak, J]] | ||
| + | [[Category: Nwachukwu, J C]] | ||
| + | [[Category: Protein ligand complex]] | ||
| + | [[Category: Transcription]] | ||
Revision as of 13:19, 5 April 2017
Crystal Structure of the ER-alpha Ligand-binding Domain (Y537S) in complex with Oxabicyclic Heptene Sulfonate (OBHS)
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