The mineralocorticoid receptor (MR) differs from the other steroid receptors in that it responds to two physiological ligands, aldosterone and cortisol. In epithelial tissues, aldosterone selectivity is determined by 11 beta-hydroxysteroid dehydrogenase type II. In other tissues cortisol is the primary ligand; in some tissues cortisol may act as an antagonist. To better target MR, an understanding of the structural determinants of tissue and ligand-specific MR activation is required. Our focus is on interactions of the ligand-binding domain (LBD) with ligand, the N-terminal domain and putative co-regulatory molecules. Molecular modelling has identified a region in the LBD of the MR and indeed other steroid receptors that critically defines ligand-specificity for aldosterone and cortisol, yet is not part of the ligand-binding pocket. An interaction between the N-terminus and LBD observed in the MR is aldosteronedependent but is unexpectedly antagonised by cortisol. The structural basis of this interaction has been defined. We have identified proteins which interact in the presence of either aldosterone or cortisol but not both. These have been confirmed as coactivators of the full-length hMR. The structural basis of this interaction has been determined for tesmin, a ligand-discriminant coactivator of the MR. The successful identification of the structural basis of antagonism and of ligand-specific interactions of the MR may provide the basis for the development of novel MR ligands with tissue specificity. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
机构:
Ist Ricovero & Cura & Carattere Sci San Raffaele, Rome, Italy
Univ Roma Tor Vergata, Osped St Eugenio, Unit Endocrinol, Rome, ItalyTufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USA
Caprio, Massimiliano
;
Newfell, Brenna G.
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Tufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USATufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USA
Newfell, Brenna G.
;
la Sala, Andrea
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Ist Ricovero & Cura & Carattere Sci San Raffaele, Rome, ItalyTufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USA
la Sala, Andrea
;
Baur, Wendy
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Tufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USATufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USA
Baur, Wendy
;
Fabbri, Andrea
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Univ Roma Tor Vergata, Osped St Eugenio, Unit Endocrinol, Rome, ItalyTufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USA
Fabbri, Andrea
;
Rosano, Giuseppe
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Ist Ricovero & Cura & Carattere Sci San Raffaele, Rome, ItalyTufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USA
Rosano, Giuseppe
;
Mendelsohn, Michael E.
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Tufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USATufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USA
Mendelsohn, Michael E.
;
Jaffe, Iris Z.
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Tufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USATufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USA
机构:
Ist Ricovero & Cura & Carattere Sci San Raffaele, Rome, Italy
Univ Roma Tor Vergata, Osped St Eugenio, Unit Endocrinol, Rome, ItalyTufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USA
Caprio, Massimiliano
;
Newfell, Brenna G.
论文数: 0引用数: 0
h-index: 0
机构:
Tufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USATufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USA
Newfell, Brenna G.
;
la Sala, Andrea
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h-index: 0
机构:
Ist Ricovero & Cura & Carattere Sci San Raffaele, Rome, ItalyTufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USA
la Sala, Andrea
;
Baur, Wendy
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h-index: 0
机构:
Tufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USATufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USA
Baur, Wendy
;
Fabbri, Andrea
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h-index: 0
机构:
Univ Roma Tor Vergata, Osped St Eugenio, Unit Endocrinol, Rome, ItalyTufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USA
Fabbri, Andrea
;
Rosano, Giuseppe
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机构:
Ist Ricovero & Cura & Carattere Sci San Raffaele, Rome, ItalyTufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USA
Rosano, Giuseppe
;
Mendelsohn, Michael E.
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h-index: 0
机构:
Tufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USATufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USA
Mendelsohn, Michael E.
;
Jaffe, Iris Z.
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h-index: 0
机构:
Tufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USATufts Med Ctr, Mol Cardiol Res Inst, Dept Med, Div Cardiol, Boston, MA 02111 USA