4Q50

The Estrogen Receptor Alpha Ligand Binding Domain D538G Mutant in Complex with 4-hydroxytamoxifen

4Q50 の概要

• エントリーDOI: 10.2210/pdb4q50/pdb
• 関連するPDBエントリー: 4Q13
• 分子名称: Estrogen receptor, 4-HYDROXYTAMOXIFEN, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: acquired serm-resistance, breast cancer, activating mutation, serm-er structure, alpha helix, nuclear hormone receptor, hormone binding protein
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Isoform 1: Nucleus . Isoform 3: Nucleus. Nucleus: P03372
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 240155.33

構造登録者

Fanning, S.W.,Greene, G.L. (登録日: 2014-04-15, 公開日: 2015-04-15, 最終更新日: 2024-02-28)

主引用文献

Fanning, S.W.,Mayne, C.G.,Dharmarajan, V.,Carlson, K.E.,Martin, T.A.,Novick, S.J.,Toy, W.,Green, B.,Panchamukhi, S.,Katzenellenbogen, B.S.,Tajkhorshid, E.,Griffin, P.R.,Shen, Y.,Chandarlapaty, S.,Katzenellenbogen, J.A.,Greene, G.L.
Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation.
Elife, 5:-, 2016

PubMed Abstract: Somatic mutations in the estrogen receptor alpha (ERα) gene (ESR1), especially Y537S and D538G, have been linked to acquired resistance to endocrine therapies. Cell-based studies demonstrated that these mutants confer ERα constitutive activity and antiestrogen resistance and suggest that ligand-binding domain dysfunction leads to endocrine therapy resistance. Here, we integrate biophysical and structural biology data to reveal how these mutations lead to a constitutively active and antiestrogen-resistant ERα. We show that these mutant ERs recruit coactivator in the absence of hormone while their affinities for estrogen agonist (estradiol) and antagonist (4-hydroxytamoxifen) are reduced. Further, they confer antiestrogen resistance by altering the conformational dynamics of the loop connecting Helix 11 and Helix 12 in the ligand-binding domain of ERα, which leads to a stabilized agonist state and an altered antagonist state that resists inhibition.

PubMed: 26836308
DOI: 10.7554/eLife.12792

実験手法

X-RAY DIFFRACTION (3.07 Å)