Structural basis for an unexpected mode of SERM-mediated ER antagonism.
Structural basis for an unexpected mode of SERM-mediated ER antagonism.
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DOI：
10.1016/j.molcel.2005.04.014
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发表时间：
2005-05
期刊：
影响因子：
16
通讯作者：
Ya-Ling Wu;Xiaojing Yang;Zhong Ren;D. McDonnell;J. Norris;T. Willson;G. Greene
中科院分区：
文献类型：
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作者：
Ya-Ling Wu;Xiaojing Yang;Zhong Ren;D. McDonnell;J. Norris;T. Willson;G. Greene
他莫昔芬是有效的预防和治疗雌激素依赖性乳腺癌，但与子宫内膜肿瘤的发病率增加。我们报道了雌激素受体α（ERα）配体结合结构域（LBD）与结构相似的化合物GW 5638结合的晶体结构，该化合物具有治疗潜力且不刺激子宫。与他莫昔芬一样，GW 5638将羧基末端螺旋（H12）重新定位到ERα LBD中已知的共激活因子对接位点。然而，GW 5638通过与该螺旋的N末端的特异性接触重新定位H12中的残基。与他莫昔芬相反，ERα LBD暴露的疏水表面的增加与MCF-7细胞中ERα的显著不稳定相关。因此，GW 5638-ERα LBD结构揭示了一种出乎意料的SERM介导的ER拮抗作用模式，其中ERα的稳定性通过H12位置的改变而降低。这种拮抗作用的双重机制可以解释为什么GW 5638可以抑制他莫昔芬耐药的乳腺肿瘤。
Tamoxifen is effective for the prevention and treatment of estrogen-dependent breast cancers, but is associated with an increased incidence of endometrial tumors. We report the crystal structure of the estrogen receptor α (ERα) ligand binding domain (LBD) bound to the structurally similar compound GW5638, which has therapeutic potential and does not stimulate the uterus. Like tamoxifen, GW5638 relocates the carboxy-terminal helix (H12) to the known coactivator-docking site in the ERα LBD. However, GW5638 repositions residues in H12 through specific contacts with the N terminus of this helix. In contrast to tamoxifen, the resulting increase in exposed hydrophobic surface of ERα LBD correlates with a significant destabilization of ERα in MCF-7 cells. Thus, the GW5638-ERα LBD structure reveals an unexpected mode of SERM-mediated ER antagonism, in which the stability of ERα is decreased through an altered position of H12. This dual mechanism of antagonism may explain why GW5638 can inhibit tamoxifen-resistant breast tumors.