Structure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist

Pike, Ashley C.W.; Brzozowski, A.M.; Hubbard, Roderick E.; Bonn, Tomas; Thorsell, A.G.; Engström, Owe; Ljunggren, Jan; Gustafsson, Jan Åke; Carlquist, Mats

doi:10.1093/emboj/18.17.4608

Cited by 923 publications

(793 citation statements)

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“…Based on the position of -helix 12, the ER LBD in the conformations stabilised by either THC and genistein should be incapable of interacting with co-activators, and hence, transcriptionally silent. Nevertheless, genistein and THC clearly show different activities on ER in mammalian cells: Genistein is a partial agonist and THC is a pure antagonist (Pike et al, 1999;Shiau et al, 2002). The I binding pattern is in excellent agreement with the latter observation, as the genistein-ER complex recognises the  peptide while the THC-ER complex does not (see also Shiau et al, 2002).…”

Section: Page 14 Of 30supporting

confidence: 62%

“…1). In general, different positionings of -helix 12 and associated changes in other helices result in different coregulator binding surfaces and hence underlie the different physiological effects of agonists and antagonists (Brzozowski et al, 1997;Pike et al 1999;Pike et al 2001;Shiau et al, 2002) (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, the side chain of partial agonists like 4-hydroxytamoxifen (OHT) partially pushes -helix 12 away, forcing it into a conformation in which it binds to the co-activator binding site and reduces the affinity for the co-activator. The side chain of pure antagonists like ICI 182,780 binds directly to the co-activator binding site, preventing co-activator binding and causing -helix 12 to be completely disordered (Brzozowski et al, 1997;Pike et al 1999;Pike et al 2001). Surprisingly, some compounds with similar antagonistic structure, such as raloxifene, are so-called selective oestrogen receptor modulators or SERMs, i.e., they are agonists in some tissues but antagonists in other.…”

Section: Introductionmentioning

confidence: 99%

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Novel modes of oestrogen receptor agonism and antagonism by hydroxylated and chlorinated biphenyls, revealed by conformation-specific peptide recognition patterns

Sumbayev

Jensen

Hansen

et al. 2008

Molecular and Cellular Endocrinology

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Please cite this article as: Sumbayev, V.V., Jensen, J.K., Hansen, J.A., Andreasen, P.A., Novel modes of oestrogen receptor agonism and antagonism by hydroxylated and chlorinated biphenyls, revealed by conformation-specific peptide recognition patterns, Molecular and Cellular Endocrinology (2007), doi:10.1016/j.mce.2008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. defined by X-ray crystal structure analysis of receptors in complex with the side chain-less 5,11-cis-diethyl-5,6,11,12-tetrahydrochrysene-2,8-diol (THC). We have now used the ability of peptides selected from phagedisplayed peptide libraries to bind conformation-specifically to oestrogen receptor- and - LBDs to analyse conformations induced by THC and a group of chlorinated biphenyls and their aryl-hydroxylated metabolites, suspected of being environmental chemical disruptors. In oestrogen receptor- THC defined a "passive antagonist" peptide recognition pattern, which was also induced by several antagonistic hydroxylated biphenyls, while a clearly different peptide recognition pattern was induced by their chlorinated agonistic counterparts. In oestrogen receptor-, THC induced a conformation similar to that induced by oestriol and other oestrogen receptor- agonists, which, as evaluated by site-directed mutagenesis, have a functionally important interaction with oestrogen receptor- residue His524. We conclude that the peptide recognition pattern can be used to used classify suspected environmental endocrine disruptors according the oestrogen receptor-and -conformations they induce.

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Section: Page 14 Of 30supporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel modes of oestrogen receptor agonism and antagonism by hydroxylated and chlorinated biphenyls, revealed by conformation-specific peptide recognition patterns

Sumbayev

Jensen

Hansen

et al. 2008

Molecular and Cellular Endocrinology

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“…Hydrophobic amino acids in H12 (Leu540, Met543 and Leu544) interact with the coactivator-binding groove in a manner similar to amphipathic coactivator LXXLL motifs (Shiau et al . 1998, Pike et al . 1999).…”

Section: Molecular Determinants Of Antiestrogenicitymentioning

confidence: 99%

Antiestrogens: structure-activity relationships and use in breast cancer treatment

Traboulsi

Ezzy

Gleason

et al. 2017

Journal of Molecular Endocrinology

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About 70% of breast tumors express estrogen receptor alpha (ERα), which mediates the proliferative effects of estrogens on breast epithelial cells, and are candidates for treatment with antiestrogens, steroidal or non-steroidal molecules designed to compete with estrogens and antagonize ERs. The variable patterns of activity of antiestrogens (AEs) in estrogen target tissues and the lack of systematic cross-resistance between different types of molecules have provided evidence for different mechanisms of action. AEs are typically classified as selective estrogen receptor modulators (SERMs), which display tissue-specific partial agonist activity (e.g. tamoxifen and raloxifene), or as pure AEs (e.g. fulvestrant), which enhance ERα post-translational modification by ubiquitin-like molecules and accelerate its proteasomal degradation. Characterization of second- and third-generation AEs, however, suggests the induction of diverse ERα structural conformations, resulting in variable degrees of receptor downregulation and different patterns of systemic properties in animal models and in the clinic.

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“…The most notable of these are the p160 class of steroid receptor coactivators (SRCs). 2,3 X-ray crystallography has revealed details of these NR-SRC interactions, [4][5][6][7][8][9] which are largely mediated by a short, conserved, pentapeptide LXXLL (L=leucine, X=amino acid) motif of the SRC, termed the NR box. The interaction between the estrogen receptor α (ERα) LBD and a peptide corresponding to NR box 2 of SRC1 (RHKILHRLLQE) is shown in Fig.…”

mentioning

confidence: 99%

Bicyclo[2.2.2]octanes: Close structural mimics of the nuclear receptor-binding motif of steroid receptor coactivators

Zhou¹,

Collins²,

Gunther³

et al. 2007

Bioorganic & Medicinal Chemistry Letters

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Nuclear hormone receptor (NR) function relies on association of agonist-bound receptors with steroid receptor coactivator (SRC) proteins through a small pentapeptide motif (LXXLL) of the SRC that binds to a hydrophobic groove on the NR. We have synthesized a series of bicyclo[2.2.2]octanes that are close structural mimics of the two key lysine residues of this SRC sequence as bound in the hydrophobic groove of the estrogen receptor. These bicyclic systems block the NR-SRC interaction with modest potency.Nuclear receptors (NRs) are transcription factors that control many physiological and pathological processes by directly regulating the expression of select target genes. 1 Members of the NR gene superfamily have multi-domain structures, with a conserved DNAbinding domain and a ligand-binding domain (LBD). The transcriptional activity of NRs is initiated by hormone binding that stabilizes the conformation of the LBD. When an agonist ligand binds, conformational stabilization rigidifies surface features that function as docking sites for coactivator protein complexes that are recruited to modify chromatin structure and activate RNA polymerase II. The most notable of these are the p160 class of steroid receptor coactivators (SRCs). 2,3 X-ray crystallography has revealed details of these NR-SRC interactions, 4-9 which are largely mediated by a short, conserved, pentapeptide LXXLL (L=leucine, X=amino acid) motif of the SRC, termed the NR box. The interaction between the estrogen receptor α (ERα) LBD and a peptide corresponding to NR box 2 of SRC1 (RHKILHRLLQE) is shown in Fig. 1. 5 Selected residues of the peptide interact with the LBD through a two-turn amphipathic α-helical motif that places the first and third leucine residues (L690 and L694) in a deep, solvent-exposed hydrophobic groove made up of residues from various helices of the LBD; histidine and arginine residues of the peptide (H691 and R692, removed for clarity) are solvent exposed and appear unnecessary for the interaction. 5 The intrinsic dipole moment of the coactivator α-helix is aligned with charged residues on the surface of the ERα-LBD (E542 interacts with the peptide N-terminus and K362 with its C-terminus), together forming a "charge clamp". 5The traditional strategy to block agonist signaling of NRs involves hormone antagonists (antihormones) that bind to the LBD, displacing the agonist and stabilizing alternative © 2007 Elsevier Ltd. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. An alternative approach to interrupting NR signaling is the use of compounds capable of blockin...

show abstract

Structure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist

Cited by 923 publications

References 43 publications

Novel modes of oestrogen receptor agonism and antagonism by hydroxylated and chlorinated biphenyls, revealed by conformation-specific peptide recognition patterns

Novel modes of oestrogen receptor agonism and antagonism by hydroxylated and chlorinated biphenyls, revealed by conformation-specific peptide recognition patterns

Antiestrogens: structure-activity relationships and use in breast cancer treatment

Bicyclo[2.2.2]octanes: Close structural mimics of the nuclear receptor-binding motif of steroid receptor coactivators

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