Mutation of the Androgen Receptor at Amino Acid 708 (Gly→Ala) Abolishes Partial Agonist Activity of Steroidal Antiandrogens

Térouanne, Béatrice; Nirdé, Philippe; Rabenoelina, Fanja; Bourguet, William; Sultan, Charles; Auzou, Gilles

doi:10.1124/mol.63.4.791

Cited by 16 publications

(10 citation statements)

References 30 publications

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“…In the androgen receptor (AR), alteration of G708 to alanine abolishes the partial agonist activity of steroidal anti-androgens (Terouanne et al 2003). Similarly, synthetic C-11 substituted spirolactones that normally inhibit MR are potent agonists of an hMR A773G mutant (Auzou et al 2000).…”

Section: Introductionmentioning

confidence: 99%

Differential interaction of RU486 with the progesterone and glucocorticoid receptors

Zhang

Tsai²,

Geller

2006

Journal of Molecular Endocrinology

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Steroid hormone receptor antagonists are widely used in clinical medicine, but their use is often complicated by the lack of receptor specificity to presently available drugs. We previously demonstrated an important role of a widely conserved helix 3 (H3)-helix 5 (H5) interaction in determining the sensitivity and specificity of steroid hormone receptors to receptor agonists. Intriguingly, the same H3 residues also play a crucial role in receptor antagonism; mutation of these residues alters the response of these receptors to antagonists. Given the close interaction of H3 and H5 residues at this site, we asked whether H5 residues might also play a role in the sensitivity of these receptors to antagonists. We demonstrate here that modification of H5 residues produces marked changes in the sensitivities of the glucocorticoid and progesterone receptor (PR) to RU486 antagonism. Moreover, while we confirm previous reports that alteration of the H3 residue, Gly 722 prevents RU486-mediated inhibition of the PR, we show that the corresponding substitution in the glucocorticoid receptor does not inhibit RU486-mediated receptor antagonism. Taken together, our data support the notion that RU486 binds differently to these two receptors, providing a potential target for the design of more specific antiglucocorticoid and antiprogestin drugs.

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Section: Introductionmentioning

confidence: 99%

Differential interaction of RU486 with the progesterone and glucocorticoid receptors

Zhang

Tsai²,

Geller

2006

Journal of Molecular Endocrinology

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“…The responses at low doses are particularly relevant to human health and may contribute to the etiology of a variety of endocrinerelated diseases (Dewailly et al 1994, Lebel et al 1998, Snedeker 2001. Of interest, some EACs display biphasic effects within large dose ranges (Kemppainen & Wilson 1996, vom Saal et al 1997, Maness et al 1998, Calabrese 2001a,b, Putz et al 2001a,b, Almstrup et al 2002, Terouanne et al 2003, Kohlerova & Skarda 2004. In parallel to this, the concept of hormesis has increasingly gained advocacy in recent years as a dose-response scheme for xenobiotics (Calabrese & Baldwin 2001a, Calabrese 2005.…”

Section: Discussionmentioning

confidence: 99%

“…A large body of evidence indicates that SHR-mediated adverse effects of EACs are sometimes nonlinear or even non-monotonic (i.e. U-shaped or inverted U-shaped) in dose ranges exerting no overt cytotoxicity (Kemppainen & Wilson 1996, vom Saal et al 1997, Maness et al 1998, Putz et al 2001a,b, Almstrup et al 2002, Terouanne et al 2003, Kohlerova & Skarda 2004.…”

Section: Introductionmentioning

confidence: 99%

Non-monotonic dose–response relationship in steroid hormone receptor-mediated gene expression

Li¹,

Andersen²,

Heber³

et al. 2007

Journal of Molecular Endocrinology

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Steroid hormone receptors are the targets of many environmental endocrine active chemicals (EACs) and synthetic drugs used in hormone therapy. While most of these chemical compounds have a unidirectional and monotonic effect, certain EACs can display non-monotonic dose-response behaviors and some synthetic drugs are selective endocrine modulators. Mechanisms underlying these complex endocrine behaviors have not been fully understood. By formulating an ordinary differential equation-based computational model, we investigated in this study the steady-state doseresponse behavior of exogenous steroid ligands in an endogenous hormonal background under various parameter conditions. Our simulation revealed that non-monotonic dose-responses in gene expression can arise within the classical genomic framework of steroid signaling. Specifically, when the exogenous ligand is an agonist, a U-shaped dose-response appears as a result of the inherently nonlinear process of receptor homodimerization. This U-shaped dose-response curve can be further modulated by mixed-ligand heterodimers formed between endogenous ligandbound and exogenous ligand-bound receptor monomers. When the heterodimer is transcriptionally inactive or repressive, the magnitude of U-shape increases; conversely, when the heterodimer is transcriptionally active, the magnitude of U-shape decreases. Additionally, we found that an inverted U-shaped dose-response can arise when the heterodimer is a strong transcription activator regardless of whether the exogenous ligand is an agonist or antagonist. Our work provides a novel mechanism for non-monotonic, particularly U-shaped, dose-response behaviors observed with certain steroid mimics, and may help not only understand how selective steroid receptor modulators work but also improve risk assessment for EACs.

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“…Of interest, however, these same residues involved play an important role in steroid hormone receptor antagonism as well. In the androgen receptor (AR), alteration of G708 to alanine abolishes the partial agonist activity of steroidal anti-androgens [30]. Similarly, synthetic C-11 substituted spirolactones that normally inhibit MR are potent agonists of an hMR A773G mutant [31].…”

Section: H3-h5 Interaction -A Common Theme In Steroid Hormone Receptomentioning

confidence: 99%

Helix 3–helix 5 interactions in steroid hormone receptor function

Zhang

Geller

2008

The Journal of Steroid Biochemistry and Molecular Biology

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Steroid hormones working through their receptors regulate a wide variety of physiologic processes necessary for normal homeostasis. Recent years have witnessed great advances in our understanding of how these hormones interact with their receptors, and have brought us closer to the era of directed drug design. We previously described a novel intramolecular interaction between helix 3 and helix 5 which is responsible for a Mendelian form of human hypertension. Further studies revealed that this interaction is highly conserved throughout the steroid hormone receptor family and functions as a key regulator of steroid hormone receptor sensitivity and specificity. Here, we review the contribution of helix 3-helix 5 interaction to steroid hormone receptor activity, with an eye towards how this knowledge may aid in the creation of novel therapeutic agonists and antagonists.Steroid hormones play a critical regulatory role in a wide variety of physiologic processes, including development, cellular differentiation, and maintenance of cellular homeostasis and blood pressure. Their effects are primarily achieved through activation of specific steroid hormone receptors (SHRs), a subgroup of the larger family of nuclear receptors (NRs), which are activated by specific interactions between the hormone agonist and a C-terminal ligandbinding domain (LBD). In recent years, the availability of high resolution three-dimensional structural information for the LBD of all five steroid hormone receptors has provided a detailed mechanistic understanding of steroid receptor agonism and antagonism [1][2][3][4][5][6][7][8]. Insights gained from such study have greatly improved our understanding of the molecular requirements for ligand-binding and receptor activation and inhibition, and this will prove invaluable as we move forward into the era of directed drug design. However, the relationship between ligandbinding and receptor activation remains poorly understood, and events required beyond ligandbinding for receptor activation have not been well-defined.The LBDs of NR's share a common architecture, with 12 alpha helices and one beta turn arranged around a central hydrophobic core [9]. Comparisons of the crystal structures of ligandfree and ligand bound NRs have shown that, upon ligand binding, NRs undergo a conformational change, including movement of helix 12 (H12) and a bending of helix 3 (H3) towards helix 5 (H5). The repositioned H12 aligns itself with H3 and H5 to form a pocket where transcriptional coactivators bind [9,10]. In recent years, the precise ligand-receptor contacts which allow these molecular events to occur have begun to be elucidated. Residues within the LBDs of nuclear receptors which interact with specific steroid functional groups have been identified, providing a structural basis for the steroid specificity of these receptors [11][12][13][14][15][16][17]. For example, in the human mineralocorticoid receptor (hMR), conserved residues in H3 and H5, Q776 and R817, form hydrogen bonds with the 3-ketone group o...

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Mutation of the Androgen Receptor at Amino Acid 708 (Gly→Ala) Abolishes Partial Agonist Activity of Steroidal Antiandrogens

Cited by 16 publications

References 30 publications

Differential interaction of RU486 with the progesterone and glucocorticoid receptors

Differential interaction of RU486 with the progesterone and glucocorticoid receptors

Non-monotonic dose–response relationship in steroid hormone receptor-mediated gene expression

Helix 3–helix 5 interactions in steroid hormone receptor function

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