Peptide antagonists of the human estrogen receptor
Peptide antagonists of the human estrogen receptor
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DOI：
10.1126/science.285.5428.744
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发表时间：
1999-07-30
期刊：
影响因子：
56.9
通讯作者：
McDonnell, DP
中科院分区：
文献类型：
--
作者：
Norris, JD;Paige, LA;McDonnell, DP
雌激素受体a的转录活性受不同构象状态的调节，这些构象状态是配体结合的结果。噬菌体展示用于鉴定与雌二醇或他莫昔芬激活的雌激素受体α特异性相互作用的肽。当这些肽在细胞中与雌激素受体α共表达时，它们作为配体特异性拮抗剂起作用，这表明雌二醇激动剂和他莫昔芬部分激动剂的活性不是通过相同的机制发生的。通过靶向配体结合袋外的位点来调节雌激素受体a转录活性的能力对开发雌激素受体a拮抗剂治疗他莫昔芬难治性乳腺癌具有重要意义。
Estrogen receptor a transcriptional activity is regulated by distinct conformational states that are the result of ligand binding. Phage display was used to identify peptides that interact specifically with either estradiol- or tamoxifen-activated estrogen receptor alpha. When these peptides were coexpressed with estrogen receptor alpha in cells, they functioned as ligand-specific antagonists, indicating that estradiol-agonist and tamoxifen-partial agonist activities do not occur by the same mechanism. The ability to regulate estrogen receptor a transcriptional activity by targeting sites outside of the ligand-binding pocket has implications for the development of estrogen receptor a antagonists for the treatment of tamoxifen-refractory breast cancers.