PUBLICATION
Molecular evolution of the switch for progesterone and spironolactone from mineralocorticoid receptor agonist to antagonist
- Authors
- Fuller, P.J., Yao, Y.Z., Jin, R., He, S., Martín-Fernández, B., Young, M.J., Smith, B.J.
- ID
- ZDB-PUB-190826-3
- Date
- 2019
- Source
- Proceedings of the National Academy of Sciences of the United States of America 116(37): 18578-18583 (Journal)
- Registered Authors
- Keywords
- aldosterone, cortisol, mineralocorticoid receptor, progesterone, sodium homeostasis
- MeSH Terms
-
- Aldosterone/biosynthesis
- Amino Acid Substitution
- Animals
- Evolution, Molecular*
- Homeostasis
- Humans
- Leucine/genetics
- Ligands
- Molecular Dynamics Simulation
- Mutagenesis, Site-Directed
- Progesterone/metabolism*
- Protein Conformation, alpha-Helical/genetics
- Protein Interaction Domains and Motifs/genetics*
- Receptors, Mineralocorticoid/genetics*
- Receptors, Mineralocorticoid/metabolism
- Rodentia/genetics
- Rodentia/metabolism
- Serine/genetics
- Spironolactone/metabolism*
- Structure-Activity Relationship
- Threonine/genetics
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 31439819 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Fuller, P.J., Yao, Y.Z., Jin, R., He, S., Martín-Fernández, B., Young, M.J., Smith, B.J. (2019) Molecular evolution of the switch for progesterone and spironolactone from mineralocorticoid receptor agonist to antagonist. Proceedings of the National Academy of Sciences of the United States of America. 116(37):18578-18583.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping