Importance of the lactonic ring in the activity of steroidal antialdosterones

Peterfalvi, M; Torelli, V.; Fournex, R.; Rousseau, Guy; Claire, M.; Michaud, Annie; Corvol, Pierre

doi:10.1016/0006-2952(80)90513-4

Cited by 24 publications

(9 citation statements)

References 11 publications

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“…In contrast, the synthetic compound 6, with a 17-ketone, and testosterone, with a 17-hydroxyl group, are devoid of any affinity for the hMR. This is also the case for two glucocorticoid ligands RU26988 and RU28362 (Gomez-Sanchez and Gomez-Sanchez, 1983;Rafestin-Oblin et al, 1986) bearing a 17␤-hydroxyl moiety and a 17␣-propynyl group and also for 17O-methyl canrenoic acid, which is the opened form of the 17␥-lactonic moiety (Funder et al, 1974;Peterfalvi et al, 1980). The hMR-LBD homology model reveals that the hydroxymethyl ketone of aldosterone forms numerous contacts with the hMR through Asn-770, Phe-941, Cys-942, Thr-945, and Phe-956.…”

Section: Discussionmentioning

confidence: 77%

A Single Amino Acid Mutation of Ala-773 in the Mineralocorticoid Receptor Confers Agonist Properties to 11β-Substituted Spirolactones

et al. 2000

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Sequence analysis revealed a strong homology between the ligand-binding domain (LBD) of the human mineralocorticoid receptor (hMR) and glucocorticoid receptor (hGR). Nevertheless, steroids with bulky C11-substituents bind to hGR, unlike hMR. In this report, a mutant hMR, in which the residue Ala-773 facing the C11 steroid position was replaced by a glycine (A773G), was assayed for its capacity to bind steroids, to interact with receptor coactivators, and to stimulate transcription. The capacity of A773G to bind aldosterone and C11-substituted spirolactones was the same as that of the wild-type receptor. The agonist properties of aldosterone, as well as the antagonist feature of compounds bearing a 11␤-allenyl group and a C17-ketone function, remain unchanged. In contrast, C11-substituted steroids with a 17␥-lactonic ring displayed antagonist properties with hMR and acted as potent agonists with A773G. An agonist-dependent hMR interaction with SRC-1 was observed for both the wild-type and the mutant receptors. The hMR activation process is discussed in the light of the hMR-LBD homology model based on the structural data of the human progesterone receptor LBD.The mineralocorticoid receptor (MR) belongs to a large family of ligand-activated transcription factors that includes the other steroid receptors as well as thyroid, retinoid, and vitamin D receptors and also orphan receptors whose ligands have not yet been identified. All the members of this large family are characterized by a conserved DNA binding domain and a C-terminal ligand-binding domain (LBD) essential for chaperone protein interaction, receptor dimerization, and hormone-dependent transactivation (Arriza et al., 1987;Evans, 1988). Recently, the crystal structure of ligand-free and liganded LBDs has been solved for several nuclear receptors (NRs) (Bourguet et al., 1995;Renaud et al., 1995;Wagner et al., 1995;Wurtz et al., 1996;Brozowski et al., 1997). These crystal structures reveal a triple-layered antiparallel ␣-helical sandwich fold surrounding the ligand-binding cavity. The major difference between the ligand-free and the agonist-bound LBD is the folding back of the helix H12 toward the LBD core, allowing the binding of transcriptional coactivators (Nichols et al., 1998). Moreover, the helix H12 was demonstrated to be differently positioned after antagonist binding, preventing the coactivator-receptor interaction (Nichols et al., 1998). A three-dimensional model of the human MR (hMR)-LBD, based on the human retinoic acid receptor (hRAR␥-LBD) crystal structure, has recently been proposed that allows the docking of various ligands within the ligand-binding cavity (Fagart et al., 1998). The identification of several amino acid residues involved in the interaction with agonists and antagonists has been made by mutagenesis. Gln-776 and Arg-817, two polar residues highly conserved within the steroid receptor family, anchor the C3-ketone function, common in mineralocorticoid agonist and antagonist ligands. At the opposite side of the ligand-bindin...

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Section: Discussionmentioning

confidence: 77%

A Single Amino Acid Mutation of Ala-773 in the Mineralocorticoid Receptor Confers Agonist Properties to 11β-Substituted Spirolactones

et al. 2000

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“…In fact, the ligand density ends after the sulfur atom, suggesting that the formyl group is rotating freely. Not surprisingly, spironolactone derivatives, such as canrenone, which are modified at this position, still retain activity (33,34). Interestingly, there is no perceptible movement of the AF-2 helix in the MR-spironolactone complex.…”

Section: Structure Of Mr C808s/s810l With Cortisone-in the Mr/ Cortismentioning

confidence: 96%

A Ligand-mediated Hydrogen Bond Network Required for the Activation of the Mineralocorticoid Receptor

Bledsoe

Madauss

Holt

et al. 2005

Journal of Biological Chemistry

196

239

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Ligand binding is the first step in hormone regulation of mineralocorticoid receptor (MR) activity. Here, we report multiple crystal structures of MR (NR3C2) bound to both agonist and antagonists. These structures combined with mutagenesis studies reveal that maximal receptor activation involves an intricate ligand-mediated hydrogen bond network with Asn 770 which serves dual roles: stabilization of the loop preceding the C-terminal activation function-2 helix and direct contact with the hormone ligand. In addition, most activating ligands hydrogen bond to Thr 945 on helix 10. Structural characterization of the naturally occurring S810L mutant explains how stabilization of a helix 3/helix 5 interaction can circumvent the requirement for this hydrogen bond network. Taken together, these results explain the potency of MR activation by aldosterone, the weak activation induced by progesterone and the antihypertensive agent spironolactone, and the binding selectivity of cortisol over cortisone.

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“…It has been shown that under in vitro conditions, the presence of a lactone ring spiro to the D ring is a prerequisite for high-affinity binding (369), which is present in spironolactone as well as in its major metabolite canrenone. In vivo, the open-ring compound canrenoate is rapidly equilibrated with its conversion product canrenone, an active MR antagonist, while canrenoate is only a very weak MR ligand in vitro (369) (see Fig.…”

Section: Pharmacologymentioning

confidence: 99%

“…4). From binding studies it is known that RU 28318 is only a very weak ligand at the MR, as is canrenoate which has almost two orders of magnitude lower affinity than its counterpart canrenone (369). Both are, however, almost equally effective in vivo, as they are converted into each other and an equilibrium is rapidly established, and the same is true for RU 28318.…”

Section: Pharmacologymentioning

confidence: 99%

Nongenomic Steroid Action: Controversies, Questions, and Answers

Lösel

Falkenstein

Feuring

et al. 2003

Physiological Reviews

502

321

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Lösel, Ralf M., Elisabeth Falkenstein, Martin Feuring, Armin Schultz, Hanns-Christian Tillmann, Karin Rossol-Haseroth, and Martin Wehling. Nongenomic Steroid Action: Controversies, Questions, and Answers. Physiol Rev 83: 965–1016, 2003; 10.1152/physrev.00003.2003.—Steroids may exert their action in living cells by several ways: 1) the well-known genomic pathway, involving hormone binding to cytosolic (classic) receptors and subsequent modulation of gene expression followed by protein synthesis. 2) Alternatively, pathways are operating that do not act on the genome, therefore indicating nongenomic action. Although it is comparatively easy to confirm the nongenomic nature of a particular phenomenon observed, e.g., by using inhibitors of transcription or translation, considerable controversy exists about the identity of receptors that mediate these responses. Many different approaches have been employed to answer this question, including pharmacology, knock-out animals, and numerous biochemical studies. Evidence is presented for and against both the participation of classic receptors, or proteins closely related to them, as well as for the involvement of yet poorly understood, novel membrane steroid receptors. In addition, clinical implications for a wide array of nongenomic steroid actions are outlined.

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Importance of the lactonic ring in the activity of steroidal antialdosterones

Cited by 24 publications

References 11 publications

A Single Amino Acid Mutation of Ala-773 in the Mineralocorticoid Receptor Confers Agonist Properties to 11β-Substituted Spirolactones

A Single Amino Acid Mutation of Ala-773 in the Mineralocorticoid Receptor Confers Agonist Properties to 11β-Substituted Spirolactones

A Ligand-mediated Hydrogen Bond Network Required for the Activation of the Mineralocorticoid Receptor

Nongenomic Steroid Action: Controversies, Questions, and Answers

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