| Structural highlights
6hhp is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| NonStd Res: | |
| Gene: | SFN, HME1 (HUMAN), ESR1, ESR, NR3A1 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[1433S_HUMAN] Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. When bound to KRT17, regulates protein synthesis and epithelial cell growth by stimulating Akt/mTOR pathway (By similarity). p53-regulated inhibitor of G2/M progression. [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]
Publication Abstract from PubMed
Modulation of protein-protein interactions (PPIs) by small molecules has emerged as a valuable approach in drug discovery. Compared to direct inhibition, PPI stabilization is vastly underexplored but has strong advantages, including the ability to gain selectivity by targeting an interface formed only upon association of proteins. Here, we present the application of a site-directed screening technique based on disulfide trapping (tethering) to select for fragments that enhance the affinity between protein partners. We target the phosphorylation-dependent interaction between the hub protein 14-3-3sigma and a peptide derived from Estrogen Receptor alpha (ERalpha), an important breast cancer target that is negatively regulated by 14-3-3sigma. We identify orthosteric stabilizers that increase 14-3-3/ERalpha affinity up to 40-fold and propose the mechanism of stabilization based on X-ray crystal structures. These fragments already display partial selectivity toward ERalpha-like motifs over other representative 14-3-3 clients. This first of its kind study illustrates the potential of the tethering approach to overcome the hurdles in systematic PPI stabilizer discovery.
Site-Directed Fragment-Based Screening for the Discovery of Protein-Protein Interaction Stabilizers.,Sijbesma E, Hallenbeck KK, Leysen S, de Vink PJ, Skora L, Jahnke W, Brunsveld L, Arkin MR, Ottmann C J Am Chem Soc. 2019 Feb 19. doi: 10.1021/jacs.8b11658. PMID:30707565[19]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Sijbesma E, Hallenbeck KK, Leysen S, de Vink PJ, Skora L, Jahnke W, Brunsveld L, Arkin MR, Ottmann C. Site-Directed Fragment-Based Screening for the Discovery of Protein-Protein Interaction Stabilizers. J Am Chem Soc. 2019 Feb 19. doi: 10.1021/jacs.8b11658. PMID:30707565 doi:http://dx.doi.org/10.1021/jacs.8b11658
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