Antagonism in the humanmineralocorticoid receptor

摘要: Key residues of the human mineralocorticoid receptor (hMR) involved in recognition agonist and antagonist ligands were identified by alanine-scanning mutagenesis based on a homology model hMR ligand-binding domain. They tested for their transactivation capacity ability to bind agonists (aldosterone, cortisol) antagonists (progesterone, RU26752). The three-dimensional reveals two polar sites located at extremities elongated hydrophobic pocket. Mutations Gln776 Arg817 site I reduce affinity both affect activate transcription, suggesting that C3-ketone group, common all ligands, is anchored these conserved within nuclear steroid family. In contrast, mutations Asn770 Thr945 opposite only binding bearing C21-hydroxyl group. exhibit smaller size faster off-rate kinetics compared with not affected. light model, new mechanism antagonism proposed which AF2-AD core region destabilized loss contacts between helix H12 region.