A second binding site for hydroxytamoxifen within the coactivator-binding groove of estrogen receptor β
A second binding site for hydroxytamoxifen within the coactivator-binding groove of estrogen receptor β
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DOI：
10.1073/pnas.0510596103
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发表时间：
2006-06-27
影响因子：
11.1
通讯作者：
Burris, Thomas P.
中科院分区：
文献类型：
--
作者：
Wang, Yong;Chirgadze, Nickolay Y.;Burris, Thomas P.
有证据表明，雌激素拮抗剂4-羟基他莫昔芬（HT）不仅可以占据雌激素受体（ER）13的配体结合结构域内的核心结合口袋，而且还可以占据其表面上的第二个位点。与HT相关的配体结合结构域（LBD）的晶体结构被确定为2.2埃，并显示两个HT分子与蛋白质结合。一个位于共识配体结合口袋中，而另一个结合到与辅激活剂识别表面的疏水凹槽重叠的位点。相对于ER α-他莫昔芬结构，螺旋12已经从辅活化剂识别表面移位并占据独特的位置。尽管已经证明拮抗剂与核心配体结合口袋的结合足以诱导拮抗剂配体结合结构域构象，但这种结构表明小分子可以直接拮抗受体-辅激活因子相互作用。这些结果提供了一个直接的演示两个结合位点的HT在ER β，如先前已建议ER α通过使用生物化学方法，并代表一个小的非肽分子占据的辅激活识别位点的晶体结构。
Evidence is presented that the estrogen antagonist 4-hydroxytamoxifen (HT) can occupy not only the core binding pocket within the ligand-binding domain of estrogen receptor (ER) 13 but also a second site on its surface. The crystal structure of the ligand-binding domain (LBD) associated with HT was determined to 2.2 angstrom and revealed two molecules of HT bound to the protein. One was located in the consensus ligand-binding pocket, whereas the other bound to a site that overlaps with the hydrophobic groove of the coactivator recognition surface. Relative to the ER alpha-tamoxifen structure, helix 12 has been displaced from the coactivator recognition surface and occupies a unique position. Although it has been demonstrated that association of the antagonist with the core ligand-binding pocket is sufficient to induce an antagonist ligand-binding domain conformation, this structure suggests that small molecules may directly antagonize receptor-coactivator interactions. These results provide a direct demonstration of two binding sites for HT in ER beta, as has been previously suggested for ER alpha by using biochemical methods, and represent a crystal structure of a small nonpeptide molecule occupying the coactivator recognition site.