Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
Mol Cell Biol. 2018 Mar 29;38(8). doi: 10.1128/MCB.00453-17. Print 2018 Apr 15.
Glucocorticoid receptor β (GRβ) is associated with glucocorticoid resistance via dominant negative regulation of GRα. To better understand how GRβ functions as a dominant negative inhibitor of GRα at a molecular level, we determined the crystal structure of the ligand binding domain of GRβ complexed with the antagonist RU-486. The structure reveals that GRβ binds RU-486 in the same ligand binding pocket as GRα, and the unique C-terminal amino acids of GRβ are mostly disordered. Binding energy analysis suggests that these C-terminal residues of GRβ do not contribute to RU-486 binding. Intriguingly, the GRβ/RU-486 complex binds corepressor peptide with affinity similar to that of a GRα/RU-486 complex, despite the lack of helix 12. Our biophysical and biochemical analyses reveal that in the presence of RU-486, GRβ is found in a conformation that favors corepressor binding, potentially antagonizing GRα function. This study thus presents an unexpected molecular mechanism by which GRβ could repress transcription.
糖皮质激素受体β（GRβ）通过对 GRα 的显性负调控与糖皮质激素抵抗有关。为了更好地理解 GRβ如何作为 GRα 的显性负抑制剂在分子水平上发挥作用，我们测定了与拮抗剂 RU-486 结合的 GRβ 配体结合域的晶体结构。该结构揭示了 GRβ与 GRα相同的配体结合口袋结合 RU-486，GRβ 的独特 C 末端氨基酸大多无序。结合能分析表明，这些 GRβ 的 C 末端残基对 RU-486 的结合没有贡献。有趣的是，尽管缺乏螺旋 12，GRβ/RU-486 复合物与核心抑制剂肽的结合亲和力与 GRα/RU-486 复合物相似。我们的生物物理和生化分析表明，在 RU-486 的存在下，GRβ 处于有利于核心抑制剂结合的构象，可能拮抗 GRα 的功能。因此，这项研究提出了一个意想不到的分子机制，即 GRβ 可以抑制转录。
