1R5K

Human Estrogen Receptor alpha Ligand-Binding Domain In Complex With GW5638

1R5K の概要

• エントリーDOI: 10.2210/pdb1r5k/pdb
• 分子名称: Estrogen receptor, (2E)-3-{4-[(1E)-1,2-DIPHENYLBUT-1-ENYL]PHENYL}ACRYLIC ACID (3 entities in total)
• 機能のキーワード: alpha helix, helical sandwich, dna binding protein
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Isoform 1: Nucleus. Isoform 3: Nucleus: P03372
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 90613.97

構造登録者

Wu, Y.-L.,Yang, X.,Ren, Z.,McDonnell, D.P.,Norris, J.D.,Willson, T.M.,Greene, G.L. (登録日: 2003-10-10, 公開日: 2004-11-23, 最終更新日: 2023-08-23)

主引用文献

Wu, Y.L.,Yang, X.,Ren, Z.,McDonnell, D.P.,Norris, J.D.,Willson, T.M.,Greene, G.L.
Structural basis for an unexpected mode of SERM-mediated ER antagonism.
Mol.Cell, 18:413-424, 2005

PubMed Abstract: Tamoxifen is effective for the prevention and treatment of estrogen-dependent breast cancers, but is associated with an increased incidence of endometrial tumors. We report the crystal structure of the estrogen receptor alpha (ERalpha) ligand binding domain (LBD) bound to the structurally similar compound GW5638, which has therapeutic potential and does not stimulate the uterus. Like tamoxifen, GW5638 relocates the carboxy-terminal helix (H12) to the known coactivator-docking site in the ERalpha LBD. However, GW5638 repositions residues in H12 through specific contacts with the N terminus of this helix. In contrast to tamoxifen, the resulting increase in exposed hydrophobic surface of ERalpha LBD correlates with a significant destabilization of ERalpha in MCF-7 cells. Thus, the GW5638-ERalpha LBD structure reveals an unexpected mode of SERM-mediated ER antagonism, in which the stability of ERalpha is decreased through an altered position of H12. This dual mechanism of antagonism may explain why GW5638 can inhibit tamoxifen-resistant breast tumors.

PubMed: 15893725
DOI: 10.1016/j.molcel.2005.04.014

実験手法

X-RAY DIFFRACTION (2.7 Å)