6b0f: Difference between revisions

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<StructureSection load='6b0f' size='340' side='right'caption='[[6b0f]], [[Resolution|resolution]] 2.86&Aring;' scene=''>
<StructureSection load='6b0f' size='340' side='right'caption='[[6b0f]], [[Resolution|resolution]] 2.86&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6b0f]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6B0F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6B0F FirstGlance]. <br>
<table><tr><td colspan='2'>[[6b0f]] 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=6B0F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6B0F FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C6V:LSZ102'>C6V</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.86&#8491;</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ESR1, ESR, NR3A1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C6V:LSZ102'>C6V</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></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=6b0f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b0f OCA], [http://pdbe.org/6b0f PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6b0f RCSB], [http://www.ebi.ac.uk/pdbsum/6b0f PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6b0f ProSAT]</span></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=6b0f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b0f OCA], [https://pdbe.org/6b0f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6b0f RCSB], [https://www.ebi.ac.uk/pdbsum/6b0f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6b0f ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== 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> 
[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 ==
In breast cancer, estrogen receptor alpha (ERalpha) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERalpha positive breast cancer has long relied on endocrine therapies such as selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor degraders (SERDs). The steroid-based anti-estrogen fulvestrant (5), the only approved SERD, is effective in patients who have not previously been treated with endocrine therapy as well as in patients who have progressed after receiving other endocrine therapies. Its efficacy, however, may be limited due to its poor physicochemical properties. We describe the design and synthesis of a series of potent benzothiophene-containing compounds that exhibit oral bioavailability and preclinical activity as SERDs. This article culminates in the identification of LSZ102 (10), a compound in clinical development for the treatment of ERalpha positive breast cancer.
 
Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer.,Tria GS, Abrams T, Baird J, Burks HE, Firestone B, Gaither LA, Hamann LG, He G, Kirby CA, Kim S, Lombardo F, Macchi KJ, McDonnell DP, Mishina Y, Norris JD, Nunez J, Springer C, Sun Y, Thomsen NM, Wang C, Wang J, Yu B, Tiong-Yip CL, Peukert S J Med Chem. 2018 Mar 22. doi: 10.1021/acs.jmedchem.7b01682. PMID:29562737<ref>PMID:29562737</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6b0f" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Baird, J]]
[[Category: Baird J]]
[[Category: Kirby, C A]]
[[Category: Kirby CA]]
[[Category: Hormone receptor]]
[[Category: Nuclear receptor]]

Latest revision as of 17:19, 13 March 2024

ESTROGEN RECEPTOR ALPHA LIGAND BINDING DOMAIN IN COMPLEX WITH LSZ102ESTROGEN RECEPTOR ALPHA LIGAND BINDING DOMAIN IN COMPLEX WITH LSZ102

Structural highlights

6b0f is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.86Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18]

See Also

References

  1. ↑ Stein B, Yang MX. Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-kappa B and C/EBP beta. Mol Cell Biol. 1995 Sep;15(9):4971-9. PMID:7651415
  2. ↑ Flouriot G, Brand H, Denger S, Metivier R, Kos M, Reid G, Sonntag-Buck V, Gannon F. Identification of a new isoform of the human estrogen receptor-alpha (hER-alpha) that is encoded by distinct transcripts and that is able to repress hER-alpha activation function 1. EMBO J. 2000 Sep 1;19(17):4688-700. PMID:10970861 doi:10.1093/emboj/19.17.4688
  3. ↑ Porter W, Saville B, Hoivik D, Safe S. Functional synergy between the transcription factor Sp1 and the estrogen receptor. Mol Endocrinol. 1997 Oct;11(11):1569-80. PMID:9328340
  4. ↑ Saville B, Wormke M, Wang F, Nguyen T, Enmark E, Kuiper G, Gustafsson JA, Safe S. Ligand-, cell-, and estrogen receptor subtype (alpha/beta)-dependent activation at GC-rich (Sp1) promoter elements. J Biol Chem. 2000 Feb 25;275(8):5379-87. PMID:10681512
  5. ↑ Stoner M, Wang F, Wormke M, Nguyen T, Samudio I, Vyhlidal C, Marme D, Finkenzeller G, Safe S. Inhibition of vascular endothelial growth factor expression in HEC1A endometrial cancer cells through interactions of estrogen receptor alpha and Sp3 proteins. J Biol Chem. 2000 Jul 28;275(30):22769-79. PMID:10816575 doi:10.1074/jbc.M002188200
  6. ↑ Teyssier C, Belguise K, Galtier F, Chalbos D. Characterization of the physical interaction between estrogen receptor alpha and JUN proteins. J Biol Chem. 2001 Sep 28;276(39):36361-9. Epub 2001 Jul 26. PMID:11477071 doi:10.1074/jbc.M101806200
  7. ↑ Metivier R, Penot G, Flouriot G, Pakdel F. Synergism between ERalpha transactivation function 1 (AF-1) and AF-2 mediated by steroid receptor coactivator protein-1: requirement for the AF-1 alpha-helical core and for a direct interaction between the N- and C-terminal domains. Mol Endocrinol. 2001 Nov;15(11):1953-70. PMID:11682626
  8. ↑ Merot Y, Metivier R, Penot G, Manu D, Saligaut C, Gannon F, Pakdel F, Kah O, Flouriot G. The relative contribution exerted by AF-1 and AF-2 transactivation functions in estrogen receptor alpha transcriptional activity depends upon the differentiation stage of the cell. J Biol Chem. 2004 Jun 18;279(25):26184-91. Epub 2004 Apr 12. PMID:15078875 doi:10.1074/jbc.M402148200
  9. ↑ Liu H, Liu K, Bodenner DL. Estrogen receptor inhibits interleukin-6 gene expression by disruption of nuclear factor kappaB transactivation. Cytokine. 2005 Aug 21;31(4):251-7. PMID:16043358 doi:10.1016/j.cyto.2004.12.008
  10. ↑ Rayala SK, den Hollander P, Balasenthil S, Yang Z, Broaddus RR, Kumar R. Functional regulation of oestrogen receptor pathway by the dynein light chain 1. EMBO Rep. 2005 Jun;6(6):538-44. PMID:15891768 doi:10.1038/sj.embor.7400417
  11. ↑ Rayala SK, den Hollander P, Manavathi B, Talukder AH, Song C, Peng S, Barnekow A, Kremerskothen J, Kumar R. Essential role of KIBRA in co-activator function of dynein light chain 1 in mammalian cells. J Biol Chem. 2006 Jul 14;281(28):19092-9. Epub 2006 May 9. PMID:16684779 doi:10.1074/jbc.M600021200
  12. ↑ Lambertini E, Tavanti E, Torreggiani E, Penolazzi L, Gambari R, Piva R. ERalpha and AP-1 interact in vivo with a specific sequence of the F promoter of the human ERalpha gene in osteoblasts. J Cell Physiol. 2008 Jul;216(1):101-10. doi: 10.1002/jcp.21379. PMID:18247370 doi:10.1002/jcp.21379
  13. ↑ Nettles KW, Gil G, Nowak J, Metivier R, Sharma VB, Greene GL. CBP Is a dosage-dependent regulator of nuclear factor-kappaB suppression by the estrogen receptor. Mol Endocrinol. 2008 Feb;22(2):263-72. Epub 2007 Oct 11. PMID:17932106 doi:10.1210/me.2007-0324
  14. ↑ Gionet N, Jansson D, Mader S, Pratt MA. NF-kappaB and estrogen receptor alpha interactions: Differential function in estrogen receptor-negative and -positive hormone-independent breast cancer cells. J Cell Biochem. 2009 Jun 1;107(3):448-59. doi: 10.1002/jcb.22141. PMID:19350539 doi:10.1002/jcb.22141
  15. ↑ Pradhan M, Bembinster LA, Baumgarten SC, Frasor J. Proinflammatory cytokines enhance estrogen-dependent expression of the multidrug transporter gene ABCG2 through estrogen receptor and NF{kappa}B cooperativity at adjacent response elements. J Biol Chem. 2010 Oct 8;285(41):31100-6. doi: 10.1074/jbc.M110.155309. Epub 2010 , Aug 12. PMID:20705611 doi:10.1074/jbc.M110.155309
  16. ↑ Kim KH, Toomre D, Bender JR. Splice isoform estrogen receptors as integral transmembrane proteins. Mol Biol Cell. 2011 Nov;22(22):4415-23. doi: 10.1091/mbc.E11-05-0416. Epub 2011, Sep 21. PMID:21937726 doi:10.1091/mbc.E11-05-0416
  17. ↑ Heldring N, Isaacs GD, Diehl AG, Sun M, Cheung E, Ranish JA, Kraus WL. Multiple sequence-specific DNA-binding proteins mediate estrogen receptor signaling through a tethering pathway. Mol Endocrinol. 2011 Apr;25(4):564-74. doi: 10.1210/me.2010-0425. Epub 2011 Feb, 17. PMID:21330404 doi:10.1210/me.2010-0425
  18. ↑ Pradhan M, Baumgarten SC, Bembinster LA, Frasor J. CBP mediates NF-kappaB-dependent histone acetylation and estrogen receptor recruitment to an estrogen response element in the BIRC3 promoter. Mol Cell Biol. 2012 Jan;32(2):569-75. doi: 10.1128/MCB.05869-11. Epub 2011 Nov, 14. PMID:22083956 doi:10.1128/MCB.05869-11

6b0f, resolution 2.86Å

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