Journal article
Molecular evolution of the switch for progesterone and spironolactone from mineralocorticoid receptor agonist to antagonist
PJ Fuller, YZ Yao, R Jin, S He, B Martín-Fernández, MJ Young, BJ Smith
Proceedings of the National Academy of Sciences of the United States of America | NATL ACAD SCIENCES | Published : 2019
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 lig..
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Awarded by Australian Government
Funding Acknowledgements
We thank Dr. Maria-Cristina Keightley for the gift of the ZF-4 cells, Jeana Thomas and Karen O'Keefe for preparation of the manuscript, and Sue Panckridge for preparation of the figures. This work was supported by the National Health & Medical Research Council of Australia through Project Grant 1058336 and Senior Principal Research Fellowship 1002559 (to P. J. F.). The Hudson Institute is supported by the Victorian Government's Operational Infrastructure Scheme. R. J. and S. H. acknowledge receipt of Australian Research Training Scholarships. Part of this work was undertaken using resources from the National Computational Infrastructure, which is supported by the Australian Government and provided through Intersect Australia Ltd., and through the HPC-GPGPU Facility, which was established with the assistance of LIEF Grant LE170100200.