Matsushima Ayami, Kakuta Yoshimitsu, Teramoto Takamasa, Koshiba Takumi, Liu Xiaohui, Okada Hiroyuki, Tokunaga Takatoshi, Kawabata Shun-Ichiro, Kimura Makoto, Shimohigashi Yasuyuki
Laboratory of Structure-Function Biochemistry, Department of Chemistry, Research-Education Centre of Risk Science, Faculty and Graduate School of Sciences, Kyushu University, Fukuoka 812-8581, Japan.
J Biochem. 2007 Oct;142(4):517-24. doi: 10.1093/jb/mvm158. Epub 2007 Aug 30.
Many lines of evidence reveal that bisphenol A (BPA) functions at very low doses as an endocrine disruptor. The human estrogen-related receptor gamma (ERR gamma) behaves as a constitutive activator of transcription, although the endogenous ligand is unknown. We have recently demonstrated that BPA binds strongly to ERR gamma (K(D) = 5.5 nM), but not to the estrogen receptor (ER). BPA preserves the ERR gamma's basal constitutive activity, and protects the selective ER modulator 4-hydroxytamoxifen from its deactivation of ERR gamma. In order to shed light on a molecular mechanism, we carried out the X-ray analysis of crystal structure of the ERR gamma ligand-binding domain (LBD) complexed with BPA. BPA binds to the receptor cavity without changing any internal structures of the pocket of the ERR gamma-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.
许多证据表明，双酚A（BPA）在极低剂量下就可作为一种内分泌干扰物发挥作用。人雌激素相关受体γ（ERRγ）表现为转录的组成型激活剂，但其内源性配体尚不清楚。我们最近证明，BPA与ERRγ有很强的结合力（解离常数K(D)=5.5 nM），但不与雌激素受体（ER）结合。BPA可保持ERRγ的基础组成型活性，并保护选择性雌激素调节剂4-羟基他莫昔芬不使其对ERRγ的失活作用。为了阐明其分子机制，我们对与BPA复合的ERRγ配体结合域（LBD）的晶体结构进行了X射线分析。BPA结合到受体腔中，而不会改变ERRγ-LBD无配体形式口袋的任何内部结构。两个酚羟基的氢键，一个与Glu275和Arg316都形成氢键，另一个与Asn346形成氢键，将BPA固定在口袋中，周围的疏水键，特别是与Tyr326形成的疏水键，使BPA的结合更加牢固。结果，将“激活螺旋”（螺旋12）维持在活性构象会保持受体的组成型活性。我们的结果首次证明核受体与内分泌干扰物形成复合物，为相互作用特征提供了详细的分子见解。
