Greschik Holger, Wurtz Jean-Marie, Sanglier Sarah, Bourguet William, van Dorsselaer Alain, Moras Dino, Renaud Jean-Paul
Laboratoire de Biologie et Génomique Structurales, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, B.P. 163, 67404 Illkirch, France.
Mol Cell. 2002 Feb;9(2):303-13. doi: 10.1016/s1097-2765(02)00444-6.
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.
雌激素相关受体3（ERR3）的配体结合结构域（LBD）与类固醇受体共激活因子-1（SRC-1）肽复合的晶体结构显示，在没有任何配体的情况下呈现转录活性构象。该结构解释了雌二醇为何不能以显著亲和力结合ERRs。对接先前报道的ERR拮抗剂己烯雌酚和4-羟基他莫昔芬，需要结构重排来扩大配体结合口袋，而这只有在拮抗剂LBD构象下才能实现。配体结合腔被更庞大侧链填满的突变受体在体外仍能与SRC-1相互作用，在体内具有转录活性，但不再能被己烯雌酚或4-羟基他莫昔芬有效灭活。这些结果为ERR3的非配体依赖性转录激活提供了结构和功能证据。
