Brzozowski A M, Pike A C, Dauter Z, Hubbard R E, Bonn T, Engström O, Ohman L, Greene G L, Gustafsson J A, Carlquist M
Protein Structure Group, Chemistry Department, University of York, UK.
Nature. 1997 Oct 16;389(6652):753-8. doi: 10.1038/39645.
Oestrogens are involved in the growth, development and homeostasis of a number of tissues. The physiological effects of these steroids are mediated by a ligand-inducible nuclear transcription factor, the oestrogen receptor (ER). Hormone binding to the ligand-binding domain (LBD) of the ER initiates a series of molecular events culminating in the activation or repression of target genes. Transcriptional regulation arises from the direct interaction of the ER with components of the cellular transcription machinery. Here we report the crystal structures of the LBD of ER in complex with the endogenous oestrogen, 17beta-oestradiol, and the selective antagonist raloxifene, at resolutions of 3.1 and 2.6 A, respectively. The structures provide a molecular basis for the distinctive pharmacophore of the ER and its catholic binding properties. Agonist and antagonist bind at the same site within the core of the LBD but demonstrate different binding modes. In addition, each class of ligand induces a distinct conformation in the transactivation domain of the LBD, providing structural evidence of the mechanism of antagonism.
雌激素参与多种组织的生长、发育和内环境稳定。这些甾体激素的生理效应由一种配体诱导型核转录因子——雌激素受体（ER）介导。激素与ER的配体结合结构域（LBD）结合会引发一系列分子事件，最终导致靶基因的激活或抑制。转录调控源于ER与细胞转录机制成分的直接相互作用。在此，我们分别报道了ER的LBD与内源性雌激素17β-雌二醇以及选择性拮抗剂雷洛昔芬复合物的晶体结构，分辨率分别为3.1 Å和2.6 Å。这些结构为ER独特的药效基团及其广泛的结合特性提供了分子基础。激动剂和拮抗剂在LBD核心区域的同一位点结合，但表现出不同的结合模式。此外，每一类配体都会在LBD的反式激活结构域诱导出独特的构象，为拮抗作用机制提供了结构证据。
