Vol. 63, Issue 4, 791-798, April 2003

Mutation of the Androgen Receptor at Amino Acid 708 (GlyAla) Abolishes Partial Agonist Activity of Steroidal Antiandrogens

Béatrice Terouanne, Philippe Nirdé, Fanja Rabenoelina, William Bourguet, Charles Sultan, and Gilles Auzou

Institut National de la Santé et de la Recherche Médicale U439, Montpellier France (B.T., P.N., F.R., C.S., G.A.); Centre de Biochimie Structurale, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/UM1, Montpellier, France (W.B); and Laboratoire d'Hormonologie du Développement et de la Reproduction, Hôpital Lapeyronie and Unité d'Endocrinologie Pédiatrique, Pédiatrie 1, CHU Hôpital A. de Villeneuve, Montpellier, France (C.S)

Mutation of a single amino acid in the ligand-binding domain (LBD) of the human androgen receptor (hAR) can induce functional abnormalities in androgen binding, stabilization of active conformation, or interaction with coactivators. The Gly708Ala and Gly708Val substitutions are associated with partial and complete androgen insensitivity syndromes, respectively. In this work, we introduced Ala, Val, and aromatic Phe mutations at position 708 on helix H3 of the hAR-LBD and tested the functional and structural consequences on hAR activity in the presence of steroidal or nonsteroidal agonists and antagonists. The residues involved in the specific recognition of these androgen ligands were identified and analyzed in the light of in vitro biological experiments and the 3D hAR-LBD structure. Our study demonstrated that the Gly708Ala mutation influenced the agonist versus antagonist activity of the ligands and confirmed the crucial role of this residue within the ligand-binding pocket (LBP) in the modulation of androgen agonists. The Gly708Ala mutation transformed the antiandrogen cyproterone acetate (CPA), a partial agonist, into a pure antiandrogen, and the pure nonsteroidal antiandrogen hydroxyflutamide in a partial agonist. From the docking studies, we suggest that CPA acts on AR through the novel mechanism called "passive antagonism".