5W9C

Estrogen Receptor Alpha Ligand Binding Domain C381S, C417S, C530S in Complex with 4-hydroxytamoxifen

Summary for 5W9C

• Entry DOI: 10.2210/pdb5w9c/pdb
• Descriptor: Estrogen receptor, 4-HYDROXYTAMOXIFEN (3 entities in total)
• Functional Keywords: breast cancer, selective estrogen receptor modulator, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 115043.02

Authors

Fanning, S.W.,Greene, G.W. (deposition date: 2017-06-23, release date: 2018-06-13, Last modification date: 2023-10-04)

Primary citation

Maximov, P.Y.,Abderrahman, B.,Fanning, S.W.,Sengupta, S.,Fan, P.,Curpan, R.F.,Rincon, D.M.Q.,Greenland, J.A.,Rajan, S.S.,Greene, G.L.,Jordan, V.C.
Endoxifen, 4-Hydroxytamoxifen and an Estrogenic Derivative Modulate Estrogen Receptor Complex Mediated Apoptosis in Breast Cancer.
Mol. Pharmacol., 94:812-822, 2018

PubMed Abstract: Estrogen therapy was used to treat advanced breast cancer in postmenopausal women for decades until the introduction of tamoxifen. Resistance to long-term estrogen deprivation (LTED) with tamoxifen and aromatase inhibitors used as a treatment of breast cancer inevitably occurs, but unexpectedly low-dose estrogen can cause regression of breast cancer and increase disease-free survival in some patients. This therapeutic effect is attributed to estrogen-induced apoptosis in LTED breast cancer. Here, we describe modulation of the estrogen receptor (ER) liganded with antiestrogens (endoxifen and 4-hydroxytamoxifen) and an estrogenic triphenylethylene (TPE), ethoxytriphenylethylene (EtOXTPE), on estrogen-induced apoptosis in LTED breast cancer cells. Our results show that the angular TPE estrogen (EtOXTPE) is able to induce the ER-mediated apoptosis only at a later time compared with planar estradiol in these cells. Using real-time polymerase chain reaction, chromatin immunoprecipitation, western blotting, molecular modeling, and X-ray crystallography techniques, we report novel conformations of the ER complex with an angular estrogen EtOXTPE and endoxifen. We propose that alteration of the conformation of the ER complexes, with changes in coactivator binding, governs estrogen-induced apoptosis through the protein kinase regulated by RNA-like endoplasmic reticulum kinase sensor system to trigger an unfolded protein response.

PubMed: 29739819
DOI: 10.1124/mol.117.111385

Experimental method

X-RAY DIFFRACTION (1.802 Å)