Pike A C, Brzozowski A M, Hubbard R E, Bonn T, Thorsell A G, Engström O, Ljunggren J, Gustafsson J A, Carlquist M
Structural Biology Laboratory, Chemistry Department, University of York, York YO10 5DD, UK.
EMBO J. 1999 Sep 1;18(17):4608-18. doi: 10.1093/emboj/18.17.4608.
Oestrogens exert their physiological effects through two receptor subtypes. Here we report the three-dimensional structure of the oestrogen receptor beta isoform (ERbeta) ligand-binding domain (LBD) in the presence of the phyto-oestrogen genistein and the antagonist raloxifene. The overall structure of ERbeta-LBD is very similar to that previously reported for ERalpha. Each ligand interacts with a unique set of residues within the hormone-binding cavity and induces a distinct orientation in the AF-2 helix (H12). The bulky side chain of raloxifene protrudes from the cavity and physically prevents the alignment of H12 over the bound ligand. In contrast, genistein is completely buried within the hydrophobic core of the protein and binds in a manner similar to that observed for ER's endogenous hormone, 17beta-oestradiol. However, in the ERbeta-genistein complex, H12 does not adopt the distinctive 'agonist' position but, instead, lies in a similar orientation to that induced by ER antagonists. Such a sub-optimal alignment of the transactivation helix is consistent with genistein's partial agonist character in ERbeta and demonstrates how ER's transcriptional response to certain bound ligands is attenuated.
雌激素通过两种受体亚型发挥其生理作用。在此，我们报道了在植物雌激素染料木黄酮和拮抗剂雷洛昔芬存在的情况下，雌激素受体β亚型（ERβ）配体结合域（LBD）的三维结构。ERβ-LBD的整体结构与先前报道的ERα非常相似。每种配体与激素结合腔内一组独特的残基相互作用，并在AF-2螺旋（H12）中诱导出不同的取向。雷洛昔芬的庞大侧链从腔内突出，从物理上阻止H12在结合配体上的排列。相比之下，染料木黄酮完全埋藏在蛋白质的疏水核心内，其结合方式与ER的内源性激素17β-雌二醇相似。然而，在ERβ-染料木黄酮复合物中，H12并未采取独特的“激动剂”位置，而是处于与ER拮抗剂诱导的取向相似的位置。反式激活螺旋的这种次优排列与染料木黄酮在ERβ中的部分激动剂特性一致，并证明了ER对某些结合配体的转录反应是如何减弱的。
