The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen
The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen
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DOI：
10.1016/s0092-8674(00)81717-1
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发表时间：
1998-12-23
期刊：
影响因子：
64.5
通讯作者：
Greene, GL
中科院分区：
文献类型：
--
作者：
Shiau, AK;Barstad, D;Greene, GL
核受体（NR）的配体依赖性转录激活通过与辅激活因子的相互作用介导。受体激动剂促进辅激活因子结合，拮抗剂阻断辅激活因子结合。在这里，我们报告的晶体结构的人雌激素受体α（hER α）配体结合域（LBD）结合激动剂己烯雌酚（DES）和一个肽来自NR盒II区的共激活GRIP 1和晶体结构的hER α LED结合选择性拮抗剂4-羟基他莫昔芬（OHT）。在DES-LBD-肽复合物中，肽作为短α螺旋与LED表面上的疏水凹槽结合。在OHT-LBD复合物中，螺旋12通过模拟NR盒肽与LED的相互作用来封闭共激活剂识别沟。这些结构揭示了OHT的结构特征促进这种“自抑制”螺旋12构象的两种不同机制。
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 LED 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 LED. In the OHT-LBD complex, helix 12 occludes the coactivator recognition groove by mimicking the interactions of the NR box peptide with the LED. These structures reveal the two distinct mechanisms by which structural features of OHT promote this "autoinhibitory" helix 12 conformation.