Structural and functional evidence for ligand-independent transcriptional activation by the estrogen-related receptor 3
Structural and functional evidence for ligand-independent transcriptional activation by the estrogen-related receptor 3
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DOI：
10.1016/s1097-2765(02)00444-6
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发表时间：
2002-02-01
期刊：
影响因子：
16
通讯作者：
Renaud, JP
中科院分区：
文献类型：
--
作者：
Greschik, H;Wurtz, JM;Renaud, JP
雌激素相关受体3（ERR 3）的配体结合结构域（LBD）与类固醇受体辅激活因子-1（SRC-1）肽复合的晶体结构揭示了在不存在任何配体的情况下的转录活性构象。该结构解释了雌二醇不以显著亲和力结合ERRs的原因。先前报道的ERR拮抗剂己烯雌酚和4-羟基他莫昔芬的对接需要结构重排，从而扩大只能与拮抗剂LBD构象相适应的配体结合口袋。其中配体结合腔被较大侧链填充的突变受体在体外仍与SRC-1相互作用，并且在体内具有转录活性，但不再被己烯雌酚或4-羟基他莫昔芬有效灭活。这些结果为ERR 3的配体非依赖性转录激活提供了结构和功能证据。
The crystal structure of the ligand binding domain (LBD) of the estrogen-related receptor 3 (ERR3) complexed with a steroid receptor coactivator-1 (SRC-1) peptide reveals a transcriptionally active conformation in absence of any ligand. The structure explains why estradiol does not bind ERRs with significant affinity. Docking of the previously reported ERR antagonists, diethylstilbestrol and 4-hydroxytamoxifen, requires structural rearrangements enlarging the ligand binding pocket that can only be accommodated with an antagonist LBD conformation. Mutant receptors in which the ligand binding cavity is filled up by bulkier side chains still interact with SRC-1 in vitro and are transcriptionally active in vivo, but are no longer efficiently inactivated by diethylstilbestrol or 4-hydroxytamoxifen. These results provide structural and functional evidence for ligand-independent transcriptional activation by ERR3.