Distinction of the binding modes for human nuclear receptor ERRγ between bisphenol A and 4-hydroxytamoxifen
Distinction of the binding modes for human nuclear receptor ERRγ between bisphenol A and 4-hydroxytamoxifen
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DOI：
10.1093/jb/mvq056
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发表时间：
2010-08-01
影响因子：
2.7
通讯作者：
Shimohigashi, Yasuyuki
中科院分区：
文献类型：
--
作者：
Liu, Xiaohui;Matsushima, Ayami;Shimohigashi, Yasuyuki
双酚A(BPA)与人雌激素相关受体γ(ERRγ)强烈结合。双酚A是一种雌激素内分泌干扰物，在很低的剂量下就会影响各种生理功能。BPA作为ERR-γ的逆型拮抗剂，通过抑制4-羟基三苯氧胺(4-OHT)的失活反向激动剂活性来保持其高的基础构效活性。我们最近证明了ERRγ受体残基Glu275和Arg316是BPA的苯酚-羟基的内在结合部位。我们还确定了苯酚-羟基Arg316氢键的重要性和苯酚-羟基Glu275氢键的佐证作用。然而，BPA和4-OHT的受体结合模式似乎有明显的不同。在本研究中，我们使用氚标记或非标记的BPA和4-OHT，详细地评估了野生型ERRγ及其275和316位氨基酸突变突变体的受体结合能力。由于Glu275和Arg316上的氢键，这两个化合物都显示出与野生型ERR伽马的强大结合能力。然而，4-OHT显示野生型和突变型受体的占有率都显著降低。所获得的数据表明，由于Glu275和Arg316具有很强的募集苯酚化合物的能力，4-OHT几乎不能与ERR伽马结合。
Bisphenol A (BPA) strongly binds to human estrogen-related receptor gamma (ERR gamma). BPA is an oestrogenic endocrine disruptor that influences various physiological functions at very low doses. BPA functions as an inverse-type antagonist of ERR gamma to retain its high basal constitutive activity by inhibiting the deactivating inverse agonist activity of 4-hydroxytamoxifen (4-OHT). We recently demonstrated that ERR gamma receptor residues Glu275 and Arg316 function as the intrinsic binding site of BPA's phenol-hydroxyl group. We also determined the chief importance of phenol-hydroxyl Arg316 hydrogen bonding and the corroborative role of phenol-hydroxyl Glu275 hydrogen bonding. However, there appeared to be a distinct difference between the receptor binding modes of BPA and 4-OHT. In the present study, using tritium-labelled or non-labelled BPA and 4-OHT, we evaluated in detail the receptor binding capabilities of wild-type ERR gamma and its mutants with amino acid alterations at positions 275 and 316. Both compounds exhibited a strong binding ability to wild-type ERR gamma due to the hydrogen bonding to Glu275 and Arg316. However, 4-OHT revealed significantly reduced occupancy for both wild-type and mutant receptors. The data obtained suggest that 4-OHT barely binds to ERR gamma due to the strong ability of Glu275 and Arg316 to recruit phenol compounds.