Receptor binding characteristics of the endocrine disruptor bisphenol A for the human nuclear estrogen-related receptor γ

Chief and corroborative hydrogen bonds of the bisphenol A phenol-hydroxyl group with Arg316 and Glu275 residues

Xiaohui Liu, Ayami Matsushima, Hiroyuki Okada, Takatoshi Tokunaga, Kaname Isozaki, Yasuyuki Shimohigashi

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

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 γ, one of 48 human nuclear receptors. Bisphenol A functions as an inverse antagonist of estrogen-related receptor γ 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 γ 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 γ-ligand-binding domain showed a strong binding ability (KD = 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-hydroxyl↔Arg316 hydrogen bonding and the corroborative role of phenol-hydroxyl↔Glu275 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 γ. These results clearly indicate that estrogen-related receptor γ forms an appropriate structure presumably to adopt an unidentified endogenous ligand.

Original languageEnglish
Pages (from-to)6340-6351
Number of pages12
JournalFEBS Journal
Volume274
Issue number24
DOIs
Publication statusPublished - Dec 1 2007

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Endocrine Disruptors
Phenol
Estrogen Receptors
Hydroxyl Radical
Hydrogen
Hydrogen bonds
Estrogens
Ligands
Hydrogen Bonding
Mutation
bisphenol A
Estrogen Antagonists
Tritium
Cytoplasmic and Nuclear Receptors
Substitution reactions
Thermodynamic properties

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

Receptor binding characteristics of the endocrine disruptor bisphenol A for the human nuclear estrogen-related receptor γ : Chief and corroborative hydrogen bonds of the bisphenol A phenol-hydroxyl group with Arg316 and Glu275 residues. / Liu, Xiaohui; Matsushima, Ayami; Okada, Hiroyuki; Tokunaga, Takatoshi; Isozaki, Kaname; Shimohigashi, Yasuyuki.

In: FEBS Journal, Vol. 274, No. 24, 01.12.2007, p. 6340-6351.

Research output: Contribution to journalArticle

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abstract = "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 γ, one of 48 human nuclear receptors. Bisphenol A functions as an inverse antagonist of estrogen-related receptor γ 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 γ 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 γ-ligand-binding domain showed a strong binding ability (KD = 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-hydroxyl↔Arg316 hydrogen bonding and the corroborative role of phenol-hydroxyl↔Glu275 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 γ. These results clearly indicate that estrogen-related receptor γ forms an appropriate structure presumably to adopt an unidentified endogenous ligand.",
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