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Structural determinants of activation of the mineralocorticoid receptor: an evolutionary perspective
- Source :
- Journal of Human Hypertension. 35:110-116
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- The mineralocorticoid receptor (MR) plays a central role in sodium homoeostasis by transducing the response to aldosterone in the distal nephron and other sodium transporting epithelia. The MR is a member of the nuclear receptor family of ligand-dependent transcription factors; it is unusual in being the receptor for two steroid hormones aldosterone and cortisol (which also binds to the closely related glucocorticoid receptor). Less well recognised is that progesterone also binds to the MR with high affinity. The conformation of the ligand-bound receptor is determined by the ligand including whether the conformation is agonist or antagonist. An agonist MR conformation then enables interactions with DNA, other MR (homodimerization) and coregulatory molecules to regulate gene expression. Insights into the structural determinants of an agonist response to ligand come from studies of the evolution of the MR. Progesterone is an agonist in the fish MR, but antagonist in the MR of terrestrial vertebrates; this switch results from the loss of a critical leucine that mediates a leucine:leucine interaction between helix 1 and helix 8 which enables the agonist response to progesterone. The insights into the intramolecular dynamics of activation suggest novel ways in which MR antagonism may be achieved beyond the current, progesterone-based antagonists in clinical use.
- Subjects :
- Agonist
Aldosterone
business.industry
medicine.drug_class
030204 cardiovascular system & hematology
Ligand (biochemistry)
Cell biology
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Mineralocorticoid receptor
Glucocorticoid receptor
Nuclear receptor
chemistry
Internal Medicine
Medicine
030212 general & internal medicine
Receptor
business
Transcription factor
Subjects
Details
- ISSN :
- 14765527 and 09509240
- Volume :
- 35
- Database :
- OpenAIRE
- Journal :
- Journal of Human Hypertension
- Accession number :
- edsair.doi...........cb93a339ca366dbdf54a879334d01f3d