A New Mode of Mineralocorticoid Receptor Antagonism by a Potent and Selective Nonsteroidal Molecule*

@article{Fagart2010ANM,
  title={A New Mode of Mineralocorticoid Receptor Antagonism by a Potent and Selective Nonsteroidal Molecule*},
  author={J{\'e}r{\^o}me Fagart and Alexander Hillisch and Jessica Huyet and Lars Baerfacker and Michèle Fay and Ulrich Pleiss and E. Pook and Stefan Sch{\"a}fer and Marie-Edith Rafestin-Oblin and Peter Kolkhof},
  journal={The Journal of Biological Chemistry},
  year={2010},
  volume={285},
  pages={29932 - 29940}
}
Limitations of current steroidal mineralocorticoid receptor (MR) antagonists have stimulated the search for a new generation of molecules. We screened for novel nonsteroidal compounds and identified MR antagonists derived from the chemical class of dihydropyridines. Chemical optimization resulted in BR-4628, which displays high in vitro and in vivo MR potency as well as selectivity with respect to the other steroid hormone receptors and the L-type calcium channel. Biochemical studies… Expand
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References

SHOWING 1-10 OF 48 REFERENCES
Structural Basis of Spirolactone Recognition by the Mineralocorticoid Receptor
TLDR
It is remarkable that the MRS810L-activating and MRWT-inactivating potencies of the C7-substituted spirolactones follow the same order, suggesting that the C 7 substituent is accommodated in the same way in MRS820L and MR WT. Expand
Antagonism in the human mineralocorticoid receptor
TLDR
A new mechanism of antagonism is proposed in which the AF2‐AD core region is destabilized by the loss of contacts between the antagonist and the helix H12 region, proposed in the light of the hMR homology model. Expand
Structural Basis for Accommodation of Nonsteroidal Ligands in the Androgen Receptor*
TLDR
These studies provide the first crystallographic evidence of the mechanism by which nonsteroid ligands interact with the wild type AR and provide critical new insight for receptor-based drug design of nonsteroidal AR agonists and antagonists. Expand
A single amino acid mutation of ala-773 in the mineralocorticoid receptor confers agonist properties to 11beta-substituted spirolactones.
TLDR
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. Expand
The ligand-dependent interaction of mineralocorticoid receptor with coactivator and corepressor peptides suggests multiple activation mechanisms.
TLDR
The coregulator and corepressor interactions with the mineralocorticoid receptor (MR) indicate that MR ligand binding domain (LBD) interacts strongly with only a few specific coactivator peptides in the presence of the agonist aldosterone and that these interactions are blocked by the antagonist eplerenone. Expand
A Ligand-mediated Hydrogen Bond Network Required for the Activation of the Mineralocorticoid Receptor*[boxs]
TLDR
Multiple crystal structures of MR (NR3C2) bound to both agonist and antagonists are reported, revealing that maximal receptor activation involves an intricate ligand-mediated hydrogen bond network with Asn770 which serves dual roles: stabilization of the loop preceding the C-terminal activation function-2 helix and direct contact with the hormone ligand. Expand
Structural and biochemical mechanisms for the specificity of hormone binding and coactivator assembly by mineralocorticoid receptor.
TLDR
This work reports a crystal structure of the MR ligand binding domain containing a single C808S mutation bound to corticosterone and the fourth LXXLL motif of steroid receptor coactivator-1 (SRC1-4) and reveals a compact steroid binding pocket with a unique topology that is primarily defined by key residues of helices 6 and 7. Expand
The Met852 Residue Is a Key Organizer of the Ligand-Binding Cavity of the Human Mineralocorticoid Receptor
TLDR
Findings indicate that Met852 acts as an organizer residue that plays two major roles: 1) it allows steroids with no substituent at the C7 position to be accommodated within the ligand-binding cavity; and 2) it is involved in the steric hindrance that prevents C7-substituted spirolactones from folding the receptor in its active state. Expand
Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonism
TLDR
Crystal structures of the ERα ligand binding domain (LBD) bound to both THC and a fragment of the transcriptional coactivator GRIP1, and the ERβ LBD bound to THC are determined and it is revealed that THC does not act on ERβ through the same mechanisms used by other known ER antagonists. Expand
Structural basis for antagonism and resistance of bicalutamide in prostate cancer
TLDR
The three-dimensional structure demonstrates that the B ring of R-bicalutamide in the W741L mutant is accommodated at the location of the indole ring of Trp-741 in the WT AR bound to dihydrotestosterone. Expand
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