7JHD

Estrogen Receptor Alpha Ligand Binding Domain Y537S in Complex with TTC-352 and GRIP Peptide

7JHD の概要

• エントリーDOI: 10.2210/pdb7jhd/pdb
• 分子名称: Estrogen receptor, Nuclear receptor coactivator 2, 3-(4-fluorophenyl)-2-(4-hydroxyphenoxy)-1-benzothiophene-6-ol, ... (4 entities in total)
• 機能のキーワード: breast cancer, synthetic agonist, drug resistance, apoptosis, transcription
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 61007.81

構造登録者

Fanning, S.W.,Abderraman, B.,Maximov, P.Y.,Jordan, V.C.,Greene, G.L. (登録日: 2020-07-20, 公開日: 2020-11-25, 最終更新日: 2023-10-18)

主引用文献

Abderrahman, B.,Maximov, P.Y.,Curpan, R.F.,Fanning, S.W.,Hanspal, J.S.,Fan, P.,Foulds, C.E.,Chen, Y.,Malovannaya, A.,Jain, A.,Xiong, R.,Greene, G.L.,Tonetti, D.A.,Thatcher, G.R.J.,Jordan, V.C.
Rapid Induction of the Unfolded Protein Response and Apoptosis by Estrogen Mimic TTC-352 for the Treatment of Endocrine-Resistant Breast Cancer.
Mol.Cancer Ther., 20:11-25, 2021

PubMed Abstract: Patients with long-term estrogen-deprived breast cancer, after resistance to tamoxifen or aromatase inhibitors develops, can experience tumor regression when treated with estrogens. Estrogen's antitumor effect is attributed to apoptosis via the estrogen receptor (ER). Estrogen treatment can have unpleasant gynecologic and nongynecologic adverse events; thus, the development of safer estrogenic agents remains a clinical priority. Here, we study synthetic selective estrogen mimics (SEM) BMI-135 and TTC-352, and the naturally occurring estrogen estetrol (E), which are proposed as safer estrogenic agents compared with 17β-estradiol (E), for the treatment of endocrine-resistant breast cancer. TTC-352 and E are being evaluated in breast cancer clinical trials. Cell viability assays, real-time PCR, immunoblotting, DNA pulldowns, mass spectrometry, X-ray crystallography, docking and molecular dynamic simulations, live cell imaging, and Annexin V staining were conducted in 11 biologically different breast cancer models. Results were compared with the potent full agonist E, less potent full agonist E, the benchmark partial agonist triphenylethylene bisphenol (BPTPE), and antagonists 4-hydroxytamoxifen and endoxifen. We report ERα's regulation and coregulators' binding profiles with SEMs and E We describe TTC-352's pharmacology as a weak full agonist and antitumor molecular mechanisms. This study highlights TTC-352's benzothiophene scaffold that yields an H-bond with Glu353, which allows Asp351-to-helix 12 (H12) interaction, sealing ERα's ligand-binding domain, recruiting E-enriched coactivators, and triggering rapid ERα-induced unfolded protein response (UPR) and apoptosis, as the basis of its anticancer properties. BPTPE's phenolic OH yields an H-Bond with Thr347, which disrupts Asp351-to-H12 interaction, delaying UPR and apoptosis and increasing clonal evolution risk.

PubMed: 33177154
DOI: 10.1158/1535-7163.MCT-20-0563

実験手法

X-RAY DIFFRACTION (2.402 Å)