Specific recognition of androgens by their nuclear receptor - A structure-function study

Androgens, like progestins, are 3-ketosteroids with structural differences restricted to the 17 beta substituent in the steroid D-ring. To better unde rstand the specific recognition of ligands by the human androgen receptor ( hAR), a homology model of the ligand-binding domain (LBD) was constructed b ased on the progesterone receptor LBD crystal structure. Several mutants of residues potentially involved in the specific recognition of ligands in th e hAR were constructed and tested for their ability to bind agonists. Their transactivation capacity in response to agonist (R1881) and antagonists (c yproterone acetate, hydroxyflutamide, and ICI 176344) was also measured. Su bstitution of His(874) by alanine, only marginally impairs the ligand-bindi ng and transactivation capacity of the hAR receptor. In contrast, mutations of Thr(877) and, to a greater extent, Asn(705) perturb ligand recognition, alter transactivation efficiency, and broaden receptor specificity. Intere stingly, the N705A mutant acquires progesterone receptor (PR) properties fo r agonist ligands but, unlike wild type AR and PR, loses the capacity to re press transactivation with nonsteroidal antagonists. Models of the hAR LBD complexes with several ligands are presented, which suggests new directions for drug design.