Structure and Function of the Steroid and Nuclear Receptor Ligand Binding Domain

SimonsJr., S. Stoney

doi:10.1007/978-1-4612-1764-0_3

Cited by 16 publications

(10 citation statements)

References 362 publications

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“…For example, ligand-free receptors are nuclear and DNA-bound for the nuclear receptors versus cytoplasmic for GR, binding of hsp90 is seen for GR and rarely for nuclear receptors (55), only the nuclear receptors heterodimerize with RXR, and the amino acids beyond helix 12 are required for ligand binding to GR (56) but not most nuclear receptors, which lack long amino acid sequences beyond helix 12. Estrogen receptors (ERs) are more like the nuclear receptors in several respects: nuclear localization of ligand-free receptors, diminished importance of hsp90 binding (57), and dispensability of COOH-terminal residues for steroid binding (58,59). Nevertheless, reports exist suggesting an interaction of coactivators with antagonist-bound ERs (60).…”

Section: Discussionmentioning

confidence: 99%

Modulation of Induction Properties of Glucocorticoid Receptor-Agonist and -Antagonist Complexes by Coactivators Involves Binding to Receptors but Is Independent of Ability of Coactivators to Augment Transactivation

He¹,

Szapary²,

Simons

2002

Journal of Biological Chemistry

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Coactivators such as TIF2 and SRC-1 modulate the positioning of the dose-response curve for agonistbound glucocorticoid receptors (GRs) and the partial agonist activity of antiglucocorticoid complexes. These properties of coactivators differ from their initially defined activities of binding to, and increasing the total levels of transactivation by, agonist-bound steroid receptors. We now report that constructs of TIF2 and SRC-1 lacking the two activation domains (AD1 and AD2) have significantly less ability to increase transactivation but retain most of the activity for modulating the dose-response curve and partial agonist activity. Mammalian two-hybrid experiments show that the minimum TIF2 segment with modulatory activity (TIF2.4) does not interact with p300, CREB-binding protein, or PCAF, which also modulates GR activities. DRIP150 and DRIP205 have been implicated in coactivator actions but are unable to modulate GR activities. The absence of synergism by PCAF or DRIP150 with SRC-1 or TIF2, respectively, further suggests that these other factors are not involved. The ability of a TIF2.4 fragment (i.e. TIF2.37), which is not known to interact with proteins, to block the actions of TIF2.4 suggests that an unidentified binder mediates the modulatory activity of TIF2. Pull-down experiments with GST/TIF2.4 demonstrate a direct interaction of TIF2 with GR in a hormone-dependent fashion that requires the receptor interaction domains of TIF2 and is equally robust with agonists and most antiglucocorticoids. These observations, which are confirmed in mammalian two-hybrid assays, suggest that the capacity of coactivators such as TIF2 to modulate the partial agonist activity of antisteroids is mediated by the binding of coactivators to GR-antagonist complexes. In conclusion, the modulatory activity of coactivators with GR-agonist and -antagonist complexes is mechanistically distinct from the ability of coactivators to augment the total levels of transactivation and appears to involve the binding to both GR-steroid complexes and an unidentified TIF2-associated factor(s).

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Section: Discussionmentioning

confidence: 99%

Modulation of Induction Properties of Glucocorticoid Receptor-Agonist and -Antagonist Complexes by Coactivators Involves Binding to Receptors but Is Independent of Ability of Coactivators to Augment Transactivation

He¹,

Szapary²,

Simons

2002

Journal of Biological Chemistry

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“…We observe a similar increase in transcriptional activity with just the LBD of Di-RXR-1. Di-RXR-1(LBD) can dimerize with EcR(LBD) (see Section 3.2), and the nuclear receptor LBD dimer is known to be enough to recruit the necessary cofactors for transcription (Simons, 1998). Since the Di-RXR-1 LBD cannot activate transcription on its own, the ligand-dependent activity seen in the presence of GAL4(DBD) -EcR(LBD) can only be due its dimerization with the EcR LBD and recruitment of the cofactors necessary for transcription.…”

Section: Di-rxr-1 Activates Transcription In Drosophila Cultured Cellsmentioning

confidence: 99%

An rxr/usp homolog from the parasitic nematode, Dirofilaria immitis

Shea¹,

Hough²,

Xiao³

et al. 2004

Gene

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“…4) and x-ray crystallographic (53,54) studies. However, earlier reports of a second site, especially with high concentrations of steroid (55), have lately attracted considerable attention (56) with the description of synergistic responses among weak estrogens (57).…”

Section: Protease Digestion Of Unactivatedmentioning

confidence: 99%

“…Thus, protease digestion studies have confirmed that steroid binding induces conformational changes in all of the members of the steroid receptor superfamily that have been examined (reviewed in Ref. 4). Even more tantalizing were the observations that antisteroids appeared to place the receptor in a conformation that rendered the carboxyl-terminal tail of the protein more susceptible to proteolytic cleavage (25).…”

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confidence: 91%

Steroid-induced Conformational Changes at Ends of the Hormone-binding Domain in the Rat Glucocorticoid Receptor Are Independent of Agonist Versus Antagonist Activity

Modarress¹,

Opoku²,

et al. 1997

Journal of Biological Chemistry

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The underlying molecular mechanism for the expression of agonist versus antagonist activity for a given receptor-steroid complex is still not known. One attractive hypothesis, based on data from progesterone receptors, is that agonist versus antagonist binding induces unique conformations at the C terminus of receptors, which can be detected by the different fragments produced by partial proteolysis. We now report that the determinants of glucocorticoid receptor (GR)-antagonist complex activity are more complex. Steroid binding did cause a conformational change in the GR that was detected by partial trypsin digestion, as described previously (Simons, S. S., Jr., Sistare, F. D., and Chakraborti, P. K. (1989) J. Biol. Chem. 264, 14493-14497). However, there was no uniformity in the digestion patterns of unactivated or activated receptors bound by a series of six structurally different antagonists including the affinity labeling antiglucocorticoid dexamethasone 21-mesylate. A total of four resistant bands were observed on SDS-polyacrylamide gels in the range of 30 -27 kDa. Using a series of point mutations and epitope-specific antibodies, it was determined that the 30-kDa species represented the entire C-terminal sequence of amino acids 518 -795, whereas the other bands arose from additional N-terminal and/or C-terminal cleavages. Bioassays with GRs containing various point and deletion mutations failed to reveal any Cterminal alterations that could convert antagonists into biologically active agonists. Thus, the presence or absence of C-terminal amino acids of the GR did not uniquely determine either the appearance of smaller trypsin-resistant fragments or the nature of the biological response of receptor-bound antisteroids. When compared with the current model of the ligand-binding domain, which is based on the x-ray structures of the comparable region of thyroid and retinoic acid receptors, the present results suggest that sequences outside of the model structure are relevant for the binding and biological activity of GRs.

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Structure and Function of the Steroid and Nuclear Receptor Ligand Binding Domain

Cited by 16 publications

References 362 publications

Modulation of Induction Properties of Glucocorticoid Receptor-Agonist and -Antagonist Complexes by Coactivators Involves Binding to Receptors but Is Independent of Ability of Coactivators to Augment Transactivation

Modulation of Induction Properties of Glucocorticoid Receptor-Agonist and -Antagonist Complexes by Coactivators Involves Binding to Receptors but Is Independent of Ability of Coactivators to Augment Transactivation

An rxr/usp homolog from the parasitic nematode, Dirofilaria immitis

Steroid-induced Conformational Changes at Ends of the Hormone-binding Domain in the Rat Glucocorticoid Receptor Are Independent of Agonist Versus Antagonist Activity

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