Abstract
The S810L mutation within the human mineralocorticoid receptor (MR S810L) induces severe hypertension and switches progesterone from antagonist to agonist. Here we report the crystal structures of the ligand-binding domain of MR S810L in complex with progesterone and deoxycorticosterone, an agonist of both wild-type and mutant MRs. These structures, the first for MR, identify the specific contacts created by Leu810 and clarify the mechanism of activation of MR S810L.
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Acknowledgements
We thank J.-L. Ferrer and M. Pirrochi from the FIP-BM30A beamline at the European Synchrotron Radiation Facility for assistance with data collection. We are also grateful to H. Richard-Foy and F. Gouilleux for providing the plasmid pFC31Luc and to S. Jalaguier for the plasmid pGEX-KG. We also thank colleagues for their critical reading of the manuscript. This work was supported by Institut National de la Santé et de la Recherche Médicale (INSERM).
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Supplementary information
Supplementary Fig. 1
Stereo view of electron density of the ligand-binding pocket of MR S810L bound to deoxycorticosterone. (PDF 892 kb)
Supplementary Fig. 2
Superimposition of the LBD of steroid receptors. (PDF 855 kb)
Supplementary Fig. 3
Binding affinity of mutant MRs. (PDF 155 kb)
Supplementary Fig. 4
Superimposition of PR and MR S810L ligand-binding pockets bound to progesterone. (PDF 397 kb)
Supplementary Table 1
Data collection and refinement statistics. (PDF 85 kb)
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Fagart, J., Huyet, J., Pinon, G. et al. Crystal structure of a mutant mineralocorticoid receptor responsible for hypertension. Nat Struct Mol Biol 12, 554–555 (2005). https://doi.org/10.1038/nsmb939
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DOI: https://doi.org/10.1038/nsmb939
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