Effect of Water Molecules on the Activating S810L Mutation of the Mineralocorticoid Receptor.

The mineralocorticoid receptor (MR) is a nuclear receptor whose endogenous ligands are mineralocorticoids, a type of steroid hormone. The activating S810L mutation is known to cause severe early-onset and pregnancy-related hypertension. Progesterone binds to the wild-type (WT) MR as a passive antagonist with fast dissociation; however, it binds to the S810L mutant as a full agonist with slow dissociation. The switch in the biological activity of progesterone is considered to be one of the causes of the disease. First, we used steered molecular dynamics simulations to analyze the dissociation process of progesterone for the WT and the S810L mutant. Progesterone in the WT dissociated from the ligand-binding pocket with a weak force in comparison with progesterone in the S810L mutant due to the large inflow of water molecules into the pocket. Therefore, we used conventional molecular dynamics simulations for the ligand-free structures of the WT and the S810L mutant to investigate the effect of the mutation on the inflow of water. In the WT, water molecules enter the ligand-binding pocket in two ways: in the vicinity of (i) Arg817 and (ii) Ser810. In contrast, few water molecules enter the pocket in the S810L mutant because of the large size and hydrophobic nature of the Leu810 side chain. Fast dissociation is a common feature among passive antagonists of MR; therefore, we inferred that the water inflow could be responsible for the dissociation kinetics of progesterone in the WT and the S810L mutant.