Structural evidence for endocrine disruptor bisphenol A binding to human nuclear receptor ERRγ

Ayami Matsushima, Yoshimitsu Kakuta, Takamasa Teramoto, Takumi Koshiba, Xiaohui Liu, Hiroyuki Okada, Takatoshi Tokunaga, Shun-Ichiro Kawabata, Makoto Kimura, Yasuyuki Shimohigashi

研究成果: ジャーナルへの寄稿記事

143 引用 (Scopus)

抄録

Many lines of evidence reveal that bisphenol A (BPA) functions at very low doses as an endocrine disruptor. The human estrogen-related receptor γ (ERRγ) behaves as a constitutive activator of transcription, although the endogenous ligand is unknown. We have recently demonstrated that BPA binds strongly to ERRγ (KD = 5.5 nM), but not to the estrogen receptor (ER). BPA preserves the ERRγ's basal constitutive activity, and protects the selective ER modulator 4-hydroxytamoxifen from its deactivation of ERRγ. In order to shed light on a molecular mechanism, we carried out the X-ray analysis of crystal structure of the ERRγ ligand-binding domain (LBD) complexed with BPA. BPA binds to the receptor cavity without changing any internal structures of the pocket of the ERRγ-LBD apo form. The hydrogen bonds of two phenol-hydroxyl groups, one with both Glu275 and Arg316, the other with Asn346, anchor BPA in the pocket, and surrounding hydrophobic bonds, especially with Tyr326, complete BPA's strong binding. Maintaining the 'activation helix' (helix 12) in an active conformation would as a result preserve receptor constitutive activity. Our results present the first evidence that the nuclear receptor forms complexes with the endocrine disruptor, providing detailed molecular insight into the interaction features.

元の言語英語
ページ(範囲)517-524
ページ数8
ジャーナルJournal of biochemistry
142
発行部数4
DOI
出版物ステータス出版済み - 10 1 2007

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Endocrine Disruptors
Cytoplasmic and Nuclear Receptors
Estrogen Receptors
Estrogens
Ligands
Selective Estrogen Receptor Modulators
X ray analysis
Transcription
Phenol
Anchors
Hydroxyl Radical
Conformations
bisphenol A
Hydrogen
Hydrogen bonds
Crystal structure
Chemical activation
X-Rays

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology

これを引用

Structural evidence for endocrine disruptor bisphenol A binding to human nuclear receptor ERRγ. / Matsushima, Ayami; Kakuta, Yoshimitsu; Teramoto, Takamasa; Koshiba, Takumi; Liu, Xiaohui; Okada, Hiroyuki; Tokunaga, Takatoshi; Kawabata, Shun-Ichiro; Kimura, Makoto; Shimohigashi, Yasuyuki.

:: Journal of biochemistry, 巻 142, 番号 4, 01.10.2007, p. 517-524.

研究成果: ジャーナルへの寄稿記事

Matsushima, A, Kakuta, Y, Teramoto, T, Koshiba, T, Liu, X, Okada, H, Tokunaga, T, Kawabata, S-I, Kimura, M & Shimohigashi, Y 2007, 'Structural evidence for endocrine disruptor bisphenol A binding to human nuclear receptor ERRγ', Journal of biochemistry, 巻. 142, 番号 4, pp. 517-524. https://doi.org/10.1093/jb/mvm158
Matsushima, Ayami ; Kakuta, Yoshimitsu ; Teramoto, Takamasa ; Koshiba, Takumi ; Liu, Xiaohui ; Okada, Hiroyuki ; Tokunaga, Takatoshi ; Kawabata, Shun-Ichiro ; Kimura, Makoto ; Shimohigashi, Yasuyuki. / Structural evidence for endocrine disruptor bisphenol A binding to human nuclear receptor ERRγ. :: Journal of biochemistry. 2007 ; 巻 142, 番号 4. pp. 517-524.
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abstract = "Many lines of evidence reveal that bisphenol A (BPA) functions at very low doses as an endocrine disruptor. The human estrogen-related receptor γ (ERRγ) behaves as a constitutive activator of transcription, although the endogenous ligand is unknown. We have recently demonstrated that BPA binds strongly to ERRγ (KD = 5.5 nM), but not to the estrogen receptor (ER). BPA preserves the ERRγ's basal constitutive activity, and protects the selective ER modulator 4-hydroxytamoxifen from its deactivation of ERRγ. In order to shed light on a molecular mechanism, we carried out the X-ray analysis of crystal structure of the ERRγ ligand-binding domain (LBD) complexed with BPA. BPA binds to the receptor cavity without changing any internal structures of the pocket of the ERRγ-LBD apo form. The hydrogen bonds of two phenol-hydroxyl groups, one with both Glu275 and Arg316, the other with Asn346, anchor BPA in the pocket, and surrounding hydrophobic bonds, especially with Tyr326, complete BPA's strong binding. Maintaining the 'activation helix' (helix 12) in an active conformation would as a result preserve receptor constitutive activity. Our results present the first evidence that the nuclear receptor forms complexes with the endocrine disruptor, providing detailed molecular insight into the interaction features.",
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AU - Kakuta, Yoshimitsu

AU - Teramoto, Takamasa

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AU - Liu, Xiaohui

AU - Okada, Hiroyuki

AU - Tokunaga, Takatoshi

AU - Kawabata, Shun-Ichiro

AU - Kimura, Makoto

AU - Shimohigashi, Yasuyuki

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