Crystallographic comparison of the estrogen and progesterone receptor's ligand binding domains
Crystallographic comparison of the estrogen and progesterone receptor's ligand binding domains
复制标题
DOI：
10.1073/pnas.95.11.5998
复制
发表时间：
1998-05-26
影响因子：
11.1
通讯作者：
Sigler, PB
中科院分区：
文献类型：
--
作者：
Tanenbaum, DM;Wang, Y;Sigler, PB
描述了雌二醇与人雌激素受体-铜配体结合域(HERαLBD)形成的配合物的2.8埃晶体结构，并与最近报道的人孕酮受体配体结合域的孕酮复合体的结构以及其他地方解决的类固醇/核受体LBD的类似结构进行了比较。荷尔蒙结合的HERαLBD形成了一个与黄体酮对应的截然不同的、可能在生理上更重要的二聚体界面。激素结合的特异性决定因素的比较揭示了一个共同的结构主题，即相互支持的范德华和涉及高度保守残基的氢键相互作用。之前提出的雌激素受体将雌二醇独特的3-羟基团与大多数其他类固醇的3-酮功能区分开来的机制，现在详细描述。突变结果的图谱指向一个共激活子结合表面，该表面包括“签名序列”周围的区域以及螺旋12，其中激活功能2核心的配体依赖的构象在所有先前解决的类固醇/核受体LBD中是相似的。在这里报道的HERαLBD中，一个特殊的晶体堆积事件取代了螺旋12，这表明这个关键的亚结构具有比预期更高的动态可变性。
The 2.8-Angstrom crystal structure of the complex formed by estradiol and the human estrogen receptor-cu ligand binding domain (hER alpha LBD) is described and compared with the recently reported structure of the progesterone complex of the human progesterone receptor ligand binding domain, as well as with similar structures of steroid/nuclear receptor LBDs solved elsewhere. The hormone-bound hER alpha LBD forms a distinctly different and probably more physiologically important dimer interface than its progesterone counterpart. A comparison of the specificity determinants of hormone binding reveals a common structural theme of mutually supported van der Waals and hydrogen-bonded interactions involving highly conserved residues. The previously suggested mechanism by which the estrogen receptor distinguishes estradiol's unique 3-hydroxy group from the 3-keto function of most other steroids is now described in atomic detail. Mapping of mutagenesis results points to a coactivator-binding surface that includes the region around the "signature sequence" as well as helix 12, where the ligand-dependent conformation of the activation function 2 core is similar in all previously solved steroid/nuclear receptor LBDs. A peculiar crystal packing event displaces helix 12 in the hER alpha LBD reported here, suggesting a higher degree of dynamic variability than expected for this critical substructure.