Shiau A K, Barstad D, Loria P M, Cheng L, Kushner P J, Agard D A, Greene G L
Howard Hughes Medical Institute and the Department of Biochemistry and Biophysics, University of California at San Francisco, 94143-0448, USA.
Cell. 1998 Dec 23;95(7):927-37. doi: 10.1016/s0092-8674(00)81717-1.
Ligand-dependent activation of transcription by nuclear receptors (NRs) is mediated by interactions with coactivators. Receptor agonists promote coactivator binding, and antagonists block coactivator binding. Here we report the crystal structure of the human estrogen receptor alpha (hER alpha) ligand-binding domain (LBD) bound to both the agonist diethylstilbestrol (DES) and a peptide derived from the NR box II region of the coactivator GRIP1 and the crystal structure of the hER alpha LBD bound to the selective antagonist 4-hydroxytamoxifen (OHT). In the DES-LBD-peptide complex, the peptide binds as a short alpha helix to a hydrophobic groove on the surface of the LBD. In the OHT-LBD complex, helix 12 occludes the coactivator recognition groove by mimicking the interactions of the NR box peptide with the LBD. These structures reveal the two distinct mechanisms by which structural features of OHT promote this "autoinhibitory" helix 12 conformation.
核受体（NRs）的配体依赖性转录激活是通过与共激活因子的相互作用介导的。受体激动剂促进共激活因子结合，而拮抗剂则阻断共激活因子结合。在此，我们报告了与激动剂己烯雌酚（DES）以及源自共激活因子GRIP1的NR框II区域的肽结合的人雌激素受体α（hERα）配体结合域（LBD）的晶体结构，以及与选择性拮抗剂4-羟基他莫昔芬（OHT）结合的hERα LBD的晶体结构。在DES-LBD-肽复合物中，该肽以短α螺旋形式结合到LBD表面的疏水凹槽上。在OHT-LBD复合物中，螺旋12通过模拟NR框肽与LBD的相互作用来封闭共激活因子识别凹槽。这些结构揭示了OHT的结构特征促进这种“自抑制性”螺旋12构象的两种不同机制。
