Structural evidence for ligand specificity in the binding domain of the human androgen receptor - Implications for pathogenic gene mutations

The crystal structures of the human androgen receptor (hAR) and human proge sterone receptor ligand-binding domains in complex with the same ligand met ribolone (R1881) have been determined. Both three-dimensional structures sh ow the typical nuclear receptor fold. The change of two residues in the lig and-binding pocket between the human progesterone receptor and hAR is most likely the source for the specificity of R1881 to the hAR. The structural i mplications of the 14 known mutations in the ligand-binding pocket of the h AR ligand-binding domains associated with either prostate cancer or the par tial or complete androgen receptor insensitivity syndrome were analyzed. Th e effects of most of these mutants could be explained on the basis of the c rystal structure.