Receptor binding characteristics of the endocrine disruptor bisphenol A for the human nuclear estrogen-related receptor [gamma]; Chief and corroborative hydrogen bonds of the bisphenol A phenol-hydroxyl group with Arg316 and Glu275 residues

Bisphenol A, 2,2-bis(4-hydroxyphenyl)propane, is an estrogenic endocrine disruptor that influences various physiological functions at very low doses, even though bisphenol A itself is ineffectual as a ligand for the estrogen receptor. We recently demonstrated that bisphenol A binds strongly to human...

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Bibliographic Details
Published in:The FEBS journal 2007-12, Vol.274 (24), p.6340
Main Authors: Liu, Xiaohui, Matsushima, Ayami, Okada, Hiroyuki, Tokunaga, Takatoshi, Isozaki, Kaname, Shimohigashi, Yasuyuki
Format: Article
Language:English
Subjects:
Binding sites
Biochemistry
Endocrine disruptors
Endocrinology
Estrogens
Hydrogen bonds
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Summary:Bisphenol A, 2,2-bis(4-hydroxyphenyl)propane, is an estrogenic endocrine disruptor that influences various physiological functions at very low doses, even though bisphenol A itself is ineffectual as a ligand for the estrogen receptor. We recently demonstrated that bisphenol A binds strongly to human estrogen-related receptor [gamma], one of 48 human nuclear receptors. Bisphenol A functions as an inverse antagonist of estrogen-related receptor [gamma] to sustain the high basal constitutive activity of the latter and to reverse the deactivating inverse agonist activity of 4-hydroxytamoxifen. However, the intrinsic binding mode of bisphenol A remains to be clarified. In the present study, we report the binding potentials between the phenol-hydroxyl group of bisphenol A and estrogen-related receptor [gamma] residues Glu275 and Arg316 in the ligand-binding domain. By inducing mutations in other amino acids, we evaluated the change in receptor binding capability of bisphenol A. Wild-type estrogen-related receptor [gamma]-ligand-binding domain showed a strong binding ability (K D = 5.70 nm) for tritium-labeled [3H]bisphenol A. Simultaneous mutation to Ala at positions 275 and 316 resulted in an absolute inability to capture bisphenol A. However, individual substitutions revealed different degrees in activity reduction, indicating the chief importance of phenol-hydroxyllArg316 hydrogen bonding and the corroborative role of phenol-hydroxyllGlu275 hydrogen bonding. The data obtained with other characteristic mutations suggested that these hydrogen bonds are conducive to the recruitment of phenol compounds by estrogen-related receptor [gamma]. These results clearly indicate that estrogen-related receptor [gamma] forms an appropriate structure presumably to adopt an unidentified endogenous ligand. [PUBLICATION ABSTRACT]
ISSN:1742-464X
1742-4658
DOI:10.1111/j.1742-4658.2007.06152.x