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Glutamic Acid 709 Substitutions Highlight the Importance of the Interaction between Androgen Receptor Helices H3 and H12 for Androgen and Antiandrogen Actions

Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 540 (V.G., S.L., C.S., J.-C.N.); Centre de Biochimie Structurale (W.B.), Centre National de la Recherche Scientifique (CNRS); Université Montpellier 1, F-34090, Montpellier, France; Laboratoire d’Hormonologie du Développement et de la Reproduction (S.L., C.S.), Hôpital Lapeyronie, Centre hospitalier Universitaire, F34 295, Montpellier, France; and Service de Pédiatrie (S.M.), Hôpital d’Enfants de Tunis, 1000 Tunis, Tunisia

Address all correspondence and requests for reprints to: Dr. Jean-Claude Nicolas, Institut National de la Santé et de la Recherche Médicale, Unité 540, Endocrinologie Moléculaire et Cellulaire des Cancers, 60 rue de Navacelles, 34090 Montpellier, France. E-mail: nicolas{at}montp.inserm.fr.

The mutation of a single amino acid in the ligand binding domain of the human androgen receptor (AR) can induce functional abnormalities; for example, in androgen binding or interactions with coregulators. We report here on the structure/function analysis of the AR_E709K substitution that is associated with partial androgen insensitivity syndrome. We introduced several mutations at position 709 and tested the consequences of these changes on AR structure and activity in the presence of androgen and antiandrogens. Our results demonstrate that a strong interaction between helix H12 and residue 709 in H3 is required to obtain a fully functional AR. We show that glutamic acid 709 can be replaced by a bulky tyrosine residue without significant effect on the activation by agonists. In contrast, smaller or linear residues that are unable to maintain a tight interaction with H12 induce a substantial loss of androgen-induced AR activity. We also show that the agonist activity of partial antiandrogens is dependent on the side-chain residue at position 709. Strikingly, the AR_E709Y substitution causes the conversion of cyproterone acetate into a pure antiandrogen and bicalutamide into a partial agonist. Together, our structural and functional data reveal the key role of glutamic acid 709 in androgenic and antiandrogenic activities.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

Coregulators:   GRIP1  |  SMRT

Ligands:   Bicalutamide  |  R1881