A characteristic back support structure in the bisphenol A-binding pocket in the human nuclear receptor ERRγ

Xiaohui Liu, Ayami Matsushima, Miki Shimohigashi, Yasuyuki Shimohigashi

研究成果: ジャーナルへの寄稿記事

13 引用 (Scopus)

抄録

The endocrine disruptor bisphenol A (BPA) affects various genes and hormones even at merely physiological levels. We recently demonstrated that BPA binds strongly to human nuclear receptor estrogen-related receptor (ERR) γ and that the phenol-A group of BPA is in a receptacle pocket with essential amino acid residues to provide structural support at the backside. This led BPA to bind to ERRγ in an induced-fit-type binding mode, for example, with a rotated motion of Val313 to support the Tyr326-binding site. A similar binding mechanism appears to occur at the binding site of the BPA phenol-B ring. X-ray crystal analysis of the ERRγ-ligand-binding domain/BPA complex suggested that the ERRγ receptor residues Leu342, Leu345, Asn346, and Ile349 function as intrinsic binding sites of the BPA phenol-B, whereas Leu265, Leu268, Ile310, Val313, Leu324, Tyr330, Lys430, Ala431, and His434 work as structural elements to assist these binding sites. In the present study, by evaluating the mutant receptors replaced by a series of amino acids, we demonstrated that a finely assembled structural network indeed exists around the two adjacent Leu342-Asn346 and Leuγ-Ileγ ridges on the same α-helix 7 (H7), constructing a part of the binding pocket structure with back support residues for the BPA phenol-B ring. The results reveal that the double-layer binding sites, namely, the ordinary ligand binding sites and their back support residues, substantiate the strong binding of BPA to ERRγ. When ERRγ-Asn346 was replaced by the corresponding Gly and Tyr in ERRα and ERRβ, respectively, the binding affinity of BPA and even 4-hydroxytamxifen (4-OHT) is much reduced. Asn346 was found to be one of the residues that make ERRc to be exclusive to BPA.

元の言語英語
記事番号e101252
ジャーナルPloS one
9
発行部数6
DOI
出版物ステータス出版済み - 6 30 2014

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bisphenol A
Cytoplasmic and Nuclear Receptors
Estrogen Receptors
receptors
estrogens
binding sites
Estrogens
Binding Sites
Phenol
phenol
estrogen receptors
Ligands
Endocrine Disruptors
endocrine-disrupting chemicals
Essential Amino Acids
essential amino acids
crystals
X-radiation
Genes
hormones

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

これを引用

A characteristic back support structure in the bisphenol A-binding pocket in the human nuclear receptor ERRγ. / Liu, Xiaohui; Matsushima, Ayami; Shimohigashi, Miki; Shimohigashi, Yasuyuki.

:: PloS one, 巻 9, 番号 6, e101252, 30.06.2014.

研究成果: ジャーナルへの寄稿記事

Liu, Xiaohui ; Matsushima, Ayami ; Shimohigashi, Miki ; Shimohigashi, Yasuyuki. / A characteristic back support structure in the bisphenol A-binding pocket in the human nuclear receptor ERRγ. :: PloS one. 2014 ; 巻 9, 番号 6.
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abstract = "The endocrine disruptor bisphenol A (BPA) affects various genes and hormones even at merely physiological levels. We recently demonstrated that BPA binds strongly to human nuclear receptor estrogen-related receptor (ERR) γ and that the phenol-A group of BPA is in a receptacle pocket with essential amino acid residues to provide structural support at the backside. This led BPA to bind to ERRγ in an induced-fit-type binding mode, for example, with a rotated motion of Val313 to support the Tyr326-binding site. A similar binding mechanism appears to occur at the binding site of the BPA phenol-B ring. X-ray crystal analysis of the ERRγ-ligand-binding domain/BPA complex suggested that the ERRγ receptor residues Leu342, Leu345, Asn346, and Ile349 function as intrinsic binding sites of the BPA phenol-B, whereas Leu265, Leu268, Ile310, Val313, Leu324, Tyr330, Lys430, Ala431, and His434 work as structural elements to assist these binding sites. In the present study, by evaluating the mutant receptors replaced by a series of amino acids, we demonstrated that a finely assembled structural network indeed exists around the two adjacent Leu342-Asn346 and Leuγ-Ileγ ridges on the same α-helix 7 (H7), constructing a part of the binding pocket structure with back support residues for the BPA phenol-B ring. The results reveal that the double-layer binding sites, namely, the ordinary ligand binding sites and their back support residues, substantiate the strong binding of BPA to ERRγ. When ERRγ-Asn346 was replaced by the corresponding Gly and Tyr in ERRα and ERRβ, respectively, the binding affinity of BPA and even 4-hydroxytamxifen (4-OHT) is much reduced. Asn346 was found to be one of the residues that make ERRc to be exclusive to BPA.",
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