Mechanistic aspects of mineralocorticoid receptor activation

Aldosterone exerts its biological effects through binding to mineralocortic oid receptor (MR). Ligand binding induces a receptor transconformation with in the ligand-binding domain and dissociation of associated proteins from t he receptor. The ligand-activated receptor hinds as a dimer to the response elements present in the promoter region of target genes and initiates the transcription through specific interactions with the transcription machiner y. The glucocorticoid hormone cortisol binds to the human MR (hMR) with the same affinity as aldosterone. bur is less efficient than aldosterone in st imulating the hMR transactivation. The antimineralocorticoid spirolactones also bind to the hMR but induce a receptor conformation that is transcripti onally silent. In this report, we describe the key residues involved in the recognition of agonist and antagonist ligands and propose a two-step model with a dynamic dimension for the MR activation. In its unliganded state, M R is in an opened conformation in which folding into the ligand-binding com petent state requires both the heat shock protein 90 and the C-terminal par t of the receptor. An intermediate complex is generated by ligand binding, leading to a more compact receptor conformation. This transient complex is then converted to a transcriptionally active conformation in which stabilit y depends on the steroid-receptor contacts.