The Structural Basis of Estrogen Receptor/Coactivator Recognition and the Antagonism of This Interaction by Tamoxifen
TL;DR: Crystal structures of the human estrogen receptor alpha (hER alpha) ligand-binding domain (LBD) and the OHT-LBD complex reveal the two distinct mechanisms by which structural features of OHT promote this "autoinhibitory" helix 12 conformation.
About: This article is published in Cell.The article was published on 1998-12-23 and is currently open access. It has received 2581 citations till now. The article focuses on the topics: Nuclear receptor coactivator 3 & Coactivator.
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TL;DR: A structural polymeric material with the ability to autonomically heal cracks is reported, which incorporates a microencapsulated healing agent that is released upon crack intrusion and polymerization of the healing agent is triggered by contact with an embedded catalyst, bonding the crack faces.
Abstract: Structural polymers are susceptible to damage in the form of cracks, which form deep within the structure where detection is difficult and repair is almost impossible. Cracking leads to mechanical degradation of fibre-reinforced polymer composites; in microelectronic polymeric components it can also lead to electrical failure. Microcracking induced by thermal and mechanical fatigue is also a long-standing problem in polymer adhesives. Regardless of the application, once cracks have formed within polymeric materials, the integrity of the structure is significantly compromised. Experiments exploring the concept of self-repair have been previously reported, but the only successful crack-healing methods that have been reported so far require some form of manual intervention. Here we report a structural polymeric material with the ability to autonomically heal cracks. The material incorporates a microencapsulated healing agent that is released upon crack intrusion. Polymerization of the healing agent is then triggered by contact with an embedded catalyst, bonding the crack faces. Our fracture experiments yield as much as 75% recovery in toughness, and we expect that our approach will be applicable to other brittle materials systems (including ceramics and glasses).
3,786 citations
TL;DR: Many proteins that lack intrinsic globular structure under physiological conditions have now been recognized, and it appears likely that their rapid turnover, aided by their unstructured nature in the unbound state, provides a level of control that allows rapid and accurate responses of the cell to changing environmental conditions.
2,804 citations
Cites background from "The Structural Basis of Estrogen Re..."
...…domain includes the LXXLL motif that has been directly implicated in nuclear receptor binding (Torchia et al., 1997; Heery et al., 1997), and which has been shown, for other coactivators, to form an a-helix upon complex formation (Nolte et al., 1998; Darimont et al., 1998; Shiau et al., 1998)....
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..., 1997), and which has been shown, for other coactivators, to form an a-helix upon complex formation (Nolte et al., 1998; Darimont et al., 1998; Shiau et al., 1998)....
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TL;DR: Using microarray-based profiling of isogenic prostate cancer xenograft models, it is found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy.
Abstract: Using microarray-based profiling of isogenic prostate cancer xenograft models, we found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy. This increase in androgen receptor mRNA and protein was both necessary and sufficient to convert prostate cancer growth from a hormone-sensitive to a hormone-refractory stage, and was dependent on a functional ligand-binding domain. Androgen receptor antagonists showed agonistic activity in cells with increased androgen receptor levels; this antagonist-agonist conversion was associated with alterations in the recruitment of coactivators and corepressors to the promoters of androgen receptor target genes. Increased levels of androgen receptor confer resistance to antiandrogens by amplifying signal output from low levels of residual ligand, and by altering the normal response to antagonists. These findings provide insight toward the design of new antiandrogens.
2,320 citations
Cites background from "The Structural Basis of Estrogen Re..."
...Because steroid receptor–antagonist complexes adopt a variety of conformation...
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TL;DR: Based on their importance in biology and medicine, as well as the relatively simple mechanism of regulation, NR represent one of the most intensively studied and best-understood classes of transcription factors at the molecular level.
Abstract: Nuclear receptors (NR) comprise a family of transcription factors that regulate gene expression in a liganddependent manner. Members of the NR superfamily include receptors for steroid hormones, such as estrogens (ER) and glucocorticoids (GR), receptors for nonsteroidal ligands, such as thyroid hormones (TR) and retinoic acid (RAR), as well as receptors that bind diverse products of lipid metabolism, such as fatty acids and prostaglandins (for review, see Beato et al. 1995; Chambon 1995; Mangelsdorf and Evans 1995). The NR superfamily also includes a large number of so-called orphan receptors for which regulatory ligands have not been identified (Mangelsdorf and Evans 1995). Although many orphan receptors are likely to be regulated by small-molecular-weight ligands, other mechanisms of regulation, such as phosphorylation (Hammer et al. 1999; Tremblay et al. 1999) have also proven to be of importance. Remarkably, the sequence of the Caenorhabditis elegans genome has revealed the presence of >200 members of the NR family, suggesting a critical role of these proteins in environmental adaptation (Sluder et al. 1999). Although mammalian genomes are unlikely to contain such a large complement of these factors, >24 distinct classes of NR have been identified in humans, and these factors exert diverse roles in the regulation of growth, development, and homeostasis. Based on their importance in biology and medicine, as well as the relatively simple mechanism of regulation, NR represent one of the most intensively studied and best-understood classes of transcription factors at the molecular level. Members of the NR family regulate transcription by several mechanisms (Fig. 1). Nuclear receptors can activate or repress target genes by binding directly to DNA response elements as homoor heterodimers or by binding to other classes of DNA-bound transcription factors. A subset of NRs, including TR and RAR, can actively repress target genes in the presence or absence of ligand binding, and many NR have been demonstrated to inhibit transcription in a ligand-dependent manner by antagonizing the transcriptional activities of other classes of transcription factors. These activities have been linked to interactions with general classes of molecules that appear to serve coactivator or corepressor function. In this review, we will discuss recent progress concerning the molecular mechanisms by which NR cofactor interactions serve to activate or repress transcription.
2,200 citations
Cites background from "The Structural Basis of Estrogen Re..."
...Intriguingly, the structures of the ER LBD bound to the antagonists raloxifene or dihydroxytamoxifen (OHT) demonstrate a distortion in the position of the AF2 helix (Brzozowski et al. 1997; Shiau et al. 1998) (Fig....
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...4A) (Darimont et al. 1998; Nolte et al. 1998; Shiau et al. 1998)....
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...In contrast, in the agonist-bound RARg, TRa, PPARg, and ER LBD structures, the AF-2 helix is tightly packed against the body of the ligand binding domain and makes direct contacts with ligand (Renaud et al. 1995; Wagner et al. 1995; Brzozowski et al. 1997; Shiau et al. 1998) (Fig....
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TL;DR: The recent successful generation of double knockout, or alpha beta ERKO mice of both sexes, suggests that this receptor is also not essential to survival and was most likely not a compensatory factor in the survival of the alpha ERKO.
Abstract: All scientific investigations begin with distinct objectives: first is the hypothesis upon which studies are undertaken to disprove, and second is the overall aim of obtaining further information, from which future and more precise hypotheses may be drawn Studies focusing on the generation and use of gene-targeted animal models also apply these goals and may be loosely categorized into sequential phases that become apparent as the use of the model progresses Initial studies of knockout models often focus on the plausibility of the model based on prior knowledge and whether the generation of an animal lacking the particular gene will prove lethal or not Upon the successful generation of a knockout, confirmatory studies are undertaken to corroborate previously established hypotheses of the function of the disrupted gene product As these studies continue, observations of unpredicted phenotypes or, more likely, the lack of a phenotype that was expected based on models put forth from past investigations are noted Often the surprising phenotype is due to the loss of a gene product that is downstream from the functions of the disrupted gene, whereas the lack of an expected phenotype may be due to compensatory roles filled by alternate mechanisms As the descriptive studies of the knockout continue, use of the model is often shifted to the role as a unique research reagent, to be used in studies that 1) were not previously possible in a wild-type model; 2) aimed at finding related proteins or pathways whose existence or functions were previously masked; or 3) the subsequent effects of the gene disruption on related physiological and biochemical systems The alpha ERKO mice continue to satisfy the confirmatory role of a knockout quite well As summarized in Table 4, the phenotypes observed in the alpha ERKO due to estrogen insensitivity have definitively illustrated several roles that were previously believed to be dependent on functional ER alpha, including 1) the proliferative and differentiative actions critical to the function of the adult female reproductive tract and mammary gland; 2) as an obligatory component in growth factor signaling in the uterus and mammary gland; 3) as the principal steroid involved in negative regulation of gonadotropin gene transcription and LH levels in the hypothalamic-pituitary axis; 4) as a positive regulator of PR expression in several tissues; 5) in the positive regulation of PRL synthesis and secretion from the pituitary; 6) as a promotional factor in oncogene-induced mammary neoplasia; and 7) as a crucial component in the differentiation and activation of several behaviors in both the female and male The list of unpredictable phenotypes in the alpha ERKO must begin with the observation that generation of an animal lacking a functional ER alpha gene was successful and produced animals of both sexes that exhibit a life span comparable to wild-type The successful generation of beta ERKO mice suggests that this receptor is also not essential to survival and was most likely not a compensatory factor in the survival of the alpha ERKO In support of this is our recent successful generation of double knockout, or alpha beta ERKO mice of both sexes The precise defects in certain components of male reproduction, including the production of abnormal sperm and the loss of intromission and ejaculatory responses that were observed in the alpha ERKO, were quite surprising In turn, certain estrogen pathways in the alpha ERKO female appear intact or unaffected, such as the ability of the uterus to successfully exhibit a progesterone-induced decidualization response, and the possible maintenance of an LH surge system in the hypothalamus [ABSTRACT TRUNCATED]
2,053 citations
References
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TL;DR: The methods presented in the chapter have been applied to solve a large variety of problems, from inorganic molecules with 5 A unit cell to rotavirus of 700 A diameters crystallized in 700 × 1000 × 1400 A cell.
Abstract: Publisher Summary X-ray data can be collected with zero-, one-, and two-dimensional detectors, zero-dimensional (single counter) being the simplest and two-dimensional the most efficient in terms of measuring diffracted X-rays in all directions. To analyze the single-crystal diffraction data collected with these detectors, several computer programs have been developed. Two-dimensional detectors and related software are now predominantly used to measure and integrate diffraction from single crystals of biological macromolecules. Macromolecular crystallography is an iterative process. To monitor the progress, the HKL package provides two tools: (1) statistics, both weighted (χ2) and unweighted (R-merge), where the Bayesian reasoning and multicomponent error model helps obtain proper error estimates and (2) visualization of the process, which helps an operator to confirm that the process of data reduction, including the resulting statistics, is correct and allows the evaluation of the problems for which there are no good statistical criteria. Visualization also provides confidence that the point of diminishing returns in data collection and reduction has been reached. At that point, the effort should be directed to solving the structure. The methods presented in the chapter have been applied to solve a large variety of problems, from inorganic molecules with 5 A unit cell to rotavirus of 700 A diameters crystallized in 700 × 1000 × 1400 A cell.
31,667 citations
"The Structural Basis of Estrogen Re..." refers methods in this paper
...…1A depicts peptide B; all other illustrations of the The images of both data sets were processed with DENZO (Otwi- coactivator peptide depict peptide A. nowski and Minor, 1997), and both data sets were scaled with SCALEPACK (Otwinowski and Minor, 1997) using the default 23s Acknowledgments cutoff....
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...Figure 1A depicts peptide B; all other illustrations of the The images of both data sets were processed with DENZO (Otwi- coactivator peptide depict peptide A. nowski and Minor, 1997), and both data sets were scaled with SCALEPACK (Otwinowski and Minor, 1997) using the default 23s Acknowledgments cutoff....
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TL;DR: The CCP4 (Collaborative Computational Project, number 4) program suite is a collection of programs and associated data and subroutine libraries which can be used for macromolecular structure determination by X-ray crystallography.
Abstract: The CCP4 (Collaborative Computational Project, number 4) program suite is a collection of programs and associated data and subroutine libraries which can be used for macromolecular structure determination by X-ray crystallography. The suite is designed to be flexible, allowing users a number of methods of achieving their aims and so there may be more than one program to cover each function. The programs are written mainly in standard Fortran77. They are from a wide variety of sources but are connected by standard data file formats. The package has been ported to all the major platforms under both Unix and VMS. The suite is distributed by anonymous ftp from Daresbury Laboratory and is widely used throughout the world.
17,220 citations
TL;DR: The likelihood function for macromolecular structures is extended to include prior phase information and experimental standard uncertainties and the results derived are consistently better than those obtained from least-squares refinement.
Abstract: This paper reviews the mathematical basis of maximum likelihood The likelihood function for macromolecular structures is extended to include prior phase information and experimental standard uncertainties The assumption that different parts of a structure might have different errors is considered A method for estimating σA using `free' reflections is described and its effects analysed The derived equations have been implemented in the program REFMAC This has been tested on several proteins at different stages of refinement (bacterial α-amylase, cytochrome c′, cross-linked insulin and oligopeptide binding protein) The results derived using the maximum-likelihood residual are consistently better than those obtained from least-squares refinement
14,622 citations
TL;DR: It is demonstrated in this work that the surface tension, water‐organic solvent, transfer‐free energies and the thermodynamics of melting of linear alkanes provide fundamental insights into the nonpolar driving forces for protein folding and protein binding reactions.
Abstract: We demonstrate in this work that the surface tension, water-organic solvent, transfer-free energies and the thermodynamics of melting of linear alkanes provide fundamental insights into the nonpolar driving forces for protein folding and protein binding reactions. We first develop a model for the curvature dependence of the hydrophobic effect and find that the macroscopic concept of interfacial free energy is applicable at the molecular level. Application of a well-known relationship involving surface tension and adhesion energies reveals that dispersion forces play little or no net role in hydrophobic interactions; rather, the standard model of disruption of water structure (entropically driven at 25 degrees C) is correct. The hydrophobic interaction is found, in agreement with the classical picture, to provide a major driving force for protein folding. Analysis of the melting behavior of hydrocarbons reveals that close packing of the protein interior makes only a small free energy contribution to folding because the enthalpic gain resulting from increased dispersion interactions (relative to the liquid) is countered by the freezing of side chain motion. The identical effect should occur in association reactions, which may provide an enormous simplification in the evaluation of binding energies. Protein binding reactions, even between nearly planar or concave/convex interfaces, are found to have effective hydrophobicities considerably smaller than the prediction based on macroscopic surface tension. This is due to the formation of a concave collar region that usually accompanies complex formation. This effect may preclude the formation of complexes between convex surfaces.
5,295 citations
"The Structural Basis of Estrogen Re..." refers background or methods in this paper
...Except for Met-421 and Met-528 (both of which con(C) A molecular surface representation of the LBD bound to DES tact only DES) and Met-388 and Ile-424 (both of which colored according to the local electrostatic potential (blue 5 posicontact only E2), the ER is able to use the same residuestive; red 5 negative) as calculated in GRASP (Nicholls et al., 1991). to form all of the observed hydrogen bonds and van derThe coactivator peptide is depicted as in (A) and the view is equivaWaals contacts with both of these distinctly shapedlent to that in (A)....
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...A crystal was briefly incubated Figures 3C and 3D were created using GRASP (Nicholls et al., 1991). in a cryoprotectant solution consisting of 10% (w/v) PEG 8000, 25% Figures 1, 2, 3A, 3B, 5, 6A, and 6D were generated using BOBSCRIPT (w/v) ethylene glycol, 50 mM HEPES (pH 7.0), and 200 mM NaCl (Esnouf, 1997) and rendered using Raster3D (Merritt and Anderson, and then flash frozen in liquid N2 suspended in a rayon loop....
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...A crystal was briefly incubated Figures 3C and 3D were created using GRASP (Nicholls et al., 1991). in a cryoprotectant solution consisting of 10% (w/v) PEG 8000, 25% Figures 1, 2, 3A, 3B, 5, 6A, and 6D were generated using BOBSCRIPT (w/v) ethylene glycol, 50 mM HEPES (pH 7.0), and 200 mM NaCl…...
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...…the local electrostatic potential (blue 5 posicontact only E2), the ER is able to use the same residuestive; red 5 negative) as calculated in GRASP (Nicholls et al., 1991). to form all of the observed hydrogen bonds and van derThe coactivator peptide is depicted as in (A) and the view is…...
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TL;DR: The LIGPLOT program automatically generates schematic 2-D representations of protein-ligand complexes from standard Protein Data Bank file input giving a simple and informative representation of the intermolecular interactions and their strengths, including hydrogen bonds, hydrophobic interactions and atom accessibilities.
Abstract: The LIGPLOT program automatically generates schematic 2-D representations of protein-ligand complexes from standard Protein Data Bank file input. The output is a colour, or black-and-white, PostScript file giving a simple and informative representation of the intermolecular interactions and their strengths, including hydrogen bonds, hydrophobic interactions and atom accessibilities. The program is completely general for any ligand and can also be used to show other types of interaction in proteins and nucleic acids. It was designed to facilitate the rapid inspection of many enzyme complexes, but has found many other applications.
4,745 citations