2b1v

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Human estrogen receptor alpha ligand-binding domain in complex with OBCP-1M and a glucocorticoid receptor interacting protein 1 NR box II peptideHuman estrogen receptor alpha ligand-binding domain in complex with OBCP-1M and a glucocorticoid receptor interacting protein 1 NR box II peptide

Structural highlights

2b1v is a 4 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 1.8Å
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]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Estrogen receptors alpha (ERalpha) and beta (ERbeta) have distinct functions and differential expression in certain tissues. These differences have stimulated the search for subtype-selective ligands. Therapeutically, such ligands offer the potential to target specific tissues or pathways regulated by one receptor subtype without affecting the other. As reagents, they can be utilized to probe the physiological functions of the ER subtypes to provide information complementary to that obtained from knock-out animals. A fluorescence resonance energy transfer-based assay was used to screen a 10,000-compound chemical library for ER agonists. From the screen, we identified a family of ERbeta-selective agonists whose members contain bulky oxabicyclic scaffolds in place of the planar scaffolds common to most ER ligands. These agonists are 10-50-fold selective for ERbeta in competitive binding assays and up to 60-fold selective in transactivation assays. The weak uterotrophic activity of these ligands in immature rats and their ability to stimulate expression of an ERbeta regulated gene in human U2OS osteosarcoma cells provides more physiological evidence of their ERbeta-selective nature. To provide insight into the molecular mechanisms of their activity and selectivity, we determined the crystal structures of the ERalpha ligand-binding domain (LBD) and a peptide from the glucocorticoid receptor-interacting protein 1 (GRIP1) coactivator complexed with the ligands OBCP-3M, OBCP-2M, and OBCP-1M. These structures illustrate how the bicyclic scaffolds of these ligands are accommodated in the flexible ligand-binding pocket of ER. A comparison of these structures with existing ER structures suggests that the ERbeta selectivity of OBCP ligands can be attributed to a combination of their interactions with Met-336 in ERbeta and Met-421 in ERalpha. These bicyclic ligands show promise as lead compounds that can target ERbeta. In addition, our understanding of the molecular determinants of their subtype selectivity provides a useful starting point for developing other ER modulators belonging to this relatively new structural class.

Identification of ligands with bicyclic scaffolds provides insights into mechanisms of estrogen receptor subtype selectivity.,Hsieh RW, Rajan SS, Sharma SK, Guo Y, DeSombre ER, Mrksich M, Greene GL J Biol Chem. 2006 Jun 30;281(26):17909-19. Epub 2006 Apr 28. PMID:16648639[19]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
  19. ↑ Hsieh RW, Rajan SS, Sharma SK, Guo Y, DeSombre ER, Mrksich M, Greene GL. Identification of ligands with bicyclic scaffolds provides insights into mechanisms of estrogen receptor subtype selectivity. J Biol Chem. 2006 Jun 30;281(26):17909-19. Epub 2006 Apr 28. PMID:16648639 doi:10.1074/jbc.M513684200

2b1v, resolution 1.80Å

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