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Research ArticleArticle

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

Béatrice Terouanne, Philippe Nirdé, Fanja Rabenoelina, William Bourguet, Charles Sultan and Gilles Auzou
Molecular Pharmacology April 2003, 63 (4) 791-798; DOI: https://doi.org/10.1124/mol.63.4.791
Béatrice Terouanne
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Philippe Nirdé
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Fanja Rabenoelina
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William Bourguet
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Charles Sultan
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Gilles Auzou
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Abstract

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”.

Footnotes

  • This work was supported by the Institut National de la Santé et de la Recherche Médicale, and grant 5205 from the Association pour la Recherche sur le Cancer.

  • Abbreviations:
    AR
    androgen receptor
    LBD
    ligand binding domain
    hAR
    human androgen receptor
    AIS
    androgen insensitivity syndrome
    DHT
    dihydrotestosterone
    CPA
    cyproterone acetate
    hMR
    human mineralocorticoid receptor
    LBP
    ligand binding pocket
    R1881
    methyltrienolone
    MGA
    megestrol acetate
    CMA
    chlormadinone acetate
    wt
    wild type
    MMTV
    murine mammary tumor virus
    CMV
    cytomegalovirus
    DCC
    dextran-coated charcoal
    FCS
    fetal calf serum
    CDTA
    trans-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid
    GA1
    11β-vinyl-3-oxo-19-nor-17α-pregna-4,9-diene-21,17-carbolactone
    • Received October 18, 2002.
    • Accepted December 17, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (4)
Molecular Pharmacology
Vol. 63, Issue 4
1 Apr 2003
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Research ArticleArticle

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

Béatrice Terouanne, Philippe Nirdé, Fanja Rabenoelina, William Bourguet, Charles Sultan and Gilles Auzou
Molecular Pharmacology April 1, 2003, 63 (4) 791-798; DOI: https://doi.org/10.1124/mol.63.4.791

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Research ArticleArticle

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

Béatrice Terouanne, Philippe Nirdé, Fanja Rabenoelina, William Bourguet, Charles Sultan and Gilles Auzou
Molecular Pharmacology April 1, 2003, 63 (4) 791-798; DOI: https://doi.org/10.1124/mol.63.4.791
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