LIGANDS FOR MINERALOCORTICOID RECEPTOR (MR) AND METHODS FOR SCREENING FOR OR DESIGNING MR LIGANDS

摘要

The inventors disclose a 1.95Å crystal structure of the MR ligand binding domain containing a single C808S mutation bound to a corticosterone and the fourth LXXLL motif of steroid receptor coactivator-1 (SRC1-4). The inventors demonstrate that SRC1-4 is the most potent MR-binding motif and mutations that disrupt the MR/ SRC1-4 interactions abolish the ability of the full-length SRC1 to coactivate MR. The structure also reveals a compact steroid binding pocket with a unique topology that is primarily defined by key residues of helices 6 and 7. Also described are novel ligands for MR, methods for screening for and designing novel MR ligands, and methods for treating MR-related diseases.