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Mutation of the Androgen Receptor at Amino Acid 708 (GlyâAla) Abolishes Partial Agonist Activity of Steroidal Antiandrogens
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 parti...
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Published in: | Molecular pharmacology 2003-04, Vol.63 (4), p.791-798 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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 âpassive antagonismâ. |
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ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.63.4.791 |