4XI3

Estrogen Receptor Alpha Ligand Binding Domain in Complex with Bazedoxifene

4XI3 の概要

• エントリーDOI: 10.2210/pdb4xi3/pdb
• 分子名称: Estrogen receptor, Bazedoxifene (3 entities in total)
• 機能のキーワード: estrogen receptor, serm, bazedoxifene, breast cancer, nuclear hormone receptor, signaling protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 112960.98

構造登録者

Fanning, S.W.,Mayne, C.G.,Toy, W.,Carlson, K.,Greene, B.,Nowak, J.,Walter, R.,Panchamukhi, S.,Tajhorshid, E.,Nettles, K.W.,Chandarlapaty, S.,Katzenellenbogen, J.,Greene, G.L. (登録日: 2015-01-06, 公開日: 2016-01-13, 最終更新日: 2024-03-06)

主引用文献

Fanning, S.W.,Jeselsohn, R.,Dharmarajan, V.,Mayne, C.G.,Karimi, M.,Buchwalter, G.,Houtman, R.,Toy, W.,Fowler, C.E.,Han, R.,Laine, M.,Carlson, K.E.,Martin, T.A.,Nowak, J.,Nwachukwu, J.C.,Hosfield, D.J.,Chandarlapaty, S.,Tajkhorshid, E.,Nettles, K.W.,Griffin, P.R.,Shen, Y.,Katzenellenbogen, J.A.,Brown, M.,Greene, G.L.
The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells.
Elife, 7:-, 2018

PubMed Abstract: Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in the (estrogen receptor alpha (ERα)) gene ligand-binding domain (LBD) represent a recognized mechanism of acquired resistance. Antiestrogens with improved efficacy versus tamoxifen might overcome the resistant phenotype in ER +breast cancers. Bazedoxifene (BZA) is a potent antiestrogen that is clinically approved for use in hormone replacement therapies. We found that BZA possesses improved inhibitory potency against the Y537S and D538G ERα mutants compared to tamoxifen and has additional inhibitory activity in combination with the CDK4/6 inhibitor palbociclib. In addition, comprehensive biophysical and structural biology studies show BZA's selective estrogen receptor degrading (SERD) properties that override the stabilizing effects of the Y537S and D538G ERα mutations.

PubMed: 30489256
DOI: 10.7554/eLife.37161

実験手法

X-RAY DIFFRACTION (2.491 Å)