Structural basis for an unexpected mode of SERM-mediated ER antagonism
作者： Ya-Ling Wu , Xiaojing Yang , Zhong Ren , Donald P. McDonnell , John D. Norris
DOI: 10.1016/J.MOLCEL.2005.04.014
关键词:
摘要: Tamoxifen is effective for the prevention and treatment of estrogen-dependent breast cancers, but associated with an increased incidence endometrial tumors. We report crystal structure estrogen receptor alpha (ERalpha) ligand binding domain (LBD) bound to structurally similar compound GW5638, which has therapeutic potential does not stimulate uterus. Like tamoxifen, GW5638 relocates carboxy-terminal helix (H12) known coactivator-docking site in ERalpha LBD. However, repositions residues H12 through specific contacts N terminus this helix. In contrast resulting increase exposed hydrophobic surface LBD correlates a significant destabilization MCF-7 cells. Thus, GW5638-ERalpha reveals unexpected mode SERM-mediated ER antagonism, stability decreased altered position H12. This dual mechanism antagonism may explain why can inhibit tamoxifen-resistant
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Marco M. Gottardis, Donald P. McDonnell, Gloria Broadwater, Timothy M. Willson, John D. Norris, Caroline E. Connor, Mark W. Dewhirst, Circumventing Tamoxifen Resistance in Breast Cancers Using Antiestrogens That Induce Unique Conformational Changes in the Estrogen Receptor Cancer Research. ,vol. 61, pp. 2917- 2922 ,(2001)
Gottardis Mm, Jordan Vc, Antitumor Actions of Keoxifene and Tamoxifen in the N-Nitrosomethylurea-induced Rat Mammary Carcinoma Model Cancer Research. ,vol. 47, pp. 4020- 4024 ,(1987)
E. vom Baur, C. Zechel, D. Heery, M. J. Heine, J. M. Garnier, V. Vivat, B. Le Douarin, H. Gronemeyer, P. Chambon, R. Losson, Differential ligand‐dependent interactions between the AF‐2 activating domain of nuclear receptors and the putative transcriptional intermediary factors mSUG1 and TIF1. The EMBO Journal. ,vol. 15, pp. 110- 124 ,(1996) , 10.1002/J.1460-2075.1996.TB00339.X
Xiao Hu, Mitchell A. Lazar, The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors Nature. ,vol. 402, pp. 93- 96 ,(1999) , 10.1038/47069
J. Don Chen, Ronald M. Evans, Transcriptional co-repressor that interacts with nuclear hormone receptors Nature. ,vol. 377, pp. 454- 457 ,(1995) , 10.1038/377454A0
David J. Bentrem, Rita C. Dardes, Hong Liu, Jennifer MacGregor-Schafer, James W. Zapf, V. Craig Jordan, Molecular mechanism of action at estrogen receptor α of a new clinically relevant antiestrogen (GW7604) related to tamoxifen Endocrinology. ,vol. 142, pp. 838- 846 ,(2001) , 10.1210/ENDO.142.2.7932
Shigehira Saji, Naoki Okumura, Hidetaka Eguchi, Shigeru Nakashima, Akio Suzuki, Masakazu Toi, Yoshinori Nozawa, Shigetoyo Saji, Shin-ichi Hayashi, MDM2 Enhances the Function of Estrogen Receptor α in Human Breast Cancer Cells Biochemical and Biophysical Research Communications. ,vol. 281, pp. 259- 265 ,(2001) , 10.1006/BBRC.2001.4339
Richard Poulin, Yves Merand, Donald Poirier, Charles Levesque, Jean-Marc Dufour, Fernand Labrie, Antiestrogenic properties of keoxifene, trans-4-hydroxytamoxifen, and ICI 164384, a new steroidal antiestrogen, in ZR-75-1 human breast cancer cells. Breast Cancer Research and Treatment. ,vol. 14, pp. 65- 76 ,(1989) , 10.1007/BF01805977
Axel T Brünger, Paul D Adams, G Marius Clore, Warren L DeLano, Piet Gros, Ralf W Grosse-Kunstleve, J-S Jiang, John Kuszewski, Michael Nilges, Navraj S Pannu, Randy J Read, Luke M Rice, Thomas Simonson, Gregory L Warren, Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination Acta Crystallographica Section D-biological Crystallography. ,vol. 54, pp. 905- 921 ,(1998) , 10.1107/S0907444998003254
Meiyun Fan, Xinghua Long, Jason A. Bailey, Chad A. Reed, Elizabeth Osborne, Edward A. Gize, Eric A. Kirk, Robert M. Bigsby, Kenneth P. Nephew, The Activating Enzyme of NEDD8 Inhibits Steroid Receptor Function Molecular Endocrinology. ,vol. 16, pp. 315- 330 ,(2002) , 10.1210/MEND.16.2.0778