ArticleProceedings of the National Academy of Sciences of the United States of America2019
Molecular evolution of the switch for progesterone and spironolactone from mineralocorticoid receptor agonist to antagonist.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 51 citations in OpenAlex.
- Human and zebrafish mineralocorticoid receptors reporter cell assays to assess the activity of chemicals.iScience · 2025Article
- In Silico Investigation of Mineralocorticoid Receptor Antagonists: Insights into Binding Mechanisms and Structural Dynamics.Molecules (Basel, Switzerland) · 2025Article
- Dynamics design of a non-natural transcription factor responding to androst-4-ene-3,17-dione.Synthetic and systems biotechnology · 2024Article
- Glucocorticoids with or without fludrocortisone in septic shock: a narrative review from a biochemical and molecular perspective.British journal of anaesthesia · 2024Review
- A comparative study of human and zebrafish glucocorticoid receptor activities of natural and pharmaceutical steroids.Frontiers in endocrinology · 2023Article
- Article
- Enhancer selection dictates gene expression responses in remote organs during tissue regeneration.Nature cell biology · 2022Article
- Aldosterone and renin concentrations were abnormally elevated in a cohort of normotensive pregnant women.Endocrine · 2022Article
- Regulation by Progestins, Corticosteroids, and RU486 of Transcriptional Activation of Elephant Shark and Human Progesterone Receptors: An Evolutionary Perspective.ACS pharmacology & translational science · 2022Article
- Domestication of farmed fishFrontiers in endocrinology · 2022Review
- Distinct regulation of hippocampal neuroplasticity and ciliary genes by corticosteroid receptors.Nature communications · 2021Article
- Structural determinants of activation of the mineralocorticoid receptor: an evolutionary perspective.Journal of human hypertension · 2021Review
- 11-Deoxycortisol controls hydromineral balance in the most basal osmoregulating vertebrate, sea lamprey (Petromyzon marinus).Scientific reports · 2020Article
- The 2020 Italian Society of Arterial Hypertension (SIIA) practical guidelines for the management of primary aldosteronism.International Journal of Cardiology. Hypertension · 2020Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The mineralocorticoid receptor (MR) is highly conserved across vertebrate evolution. In terrestrial vertebrates, the MR mediates sodium homeostasis by aldosterone and also acts as a receptor for cortisol. Although the MR is present in fish, they lack aldosterone. The MR binds progesterone and spironolactone as antagonists in human MR but as agonists in zebrafish MR. We have defined the molecular basis of these divergent responses using MR chimeras between the zebrafish and human MR coupled with reciprocal site-directed mutagenesis and molecular dynamic (MD) simulation based on the crystal structures of the MR ligand-binding domain. Substitution of a leucine by threonine in helix 8 of the ligand-binding domain of the zebrafish MR confers the antagonist response. This leucine is conserved across fish species, whereas threonine (serine in rodents) is conserved in terrestrial vertebrate MR. MD identified an interaction of the leucine in helix 8 with a highly conserved leucine in helix 1 that stabilizes the agonist conformation including the interaction between helices 3 and 5, an interaction which has previously been characterized. This switch in the MR coincides with the evolution of terrestrial vertebrates and of aldosterone synthesis. It was perhaps mandatory if the appearance of aldosterone as a specific mediator of the homeostatic salt retention was to be tolerated. The conformational changes also provide insights into the structural basis of agonism versus antagonism in steroid receptors with potential implications for drug design in this important therapeutic target.
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