Specific Recognition of Androgens by Their Nuclear Receptor

Abstract

Androgens, like progestins, are 3-ketosteroids with structural differences restricted to the 17β substituent in the steroid D-ring. To better understand the specific recognition of ligands by the human androgen receptor (hAR), a homology model of the ligand-binding domain (LBD) was constructed based on the progesterone receptor LBD crystal structure. Several mutants of residues potentially involved in the specific recognition of ligands in the hAR were constructed and tested for their ability to bind agonists. Their transactivation capacity in response to agonist (R1881) and antagonists (cyprotcrone acetate, hydroxyflutamide, and ICI 176344) was also measured. Substitution of His874 by alanine, only marginally impairs the ligand-binding and transactivation capacity of the hAR receptor. In contrast, mutations of Thr877 and, to a greater extent, Asn705 perturb ligand recognition, alter transactivation efficiency, and broaden receptor specificity. Interestingly, the N705A mutant acquires progesterone receptor (PR) properties for agonist ligands but, unlike wild type AR and PR, loses the capacity to repress transactivation with non-steroidal antagonists. Models of the hAR-LBD complexes with several ligands are presented, which suggests new directions for drug design.