3UU7

Crystal structure of hERa-LBD (Y537S) in complex with bisphenol-A

3UU7 の概要

• エントリーDOI: 10.2210/pdb3uu7/pdb
• 関連するPDBエントリー: 3UUA 3UUC 3UUD
• 分子名称: Estrogen receptor, Nuclear receptor coactivator 1, 4,4'-PROPANE-2,2-DIYLDIPHENOL, ... (5 entities in total)
• 機能のキーワード: ligand-binding domain of nuclear hormone receptor, hormone receptor
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Isoform 1: Nucleus. Isoform 3: Nucleus. Nucleus: P03372 P03372; Nucleus (By similarity): Q15788
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 60969.82

構造登録者

Delfosse, V.,Grimaldi, M.,Bourguet, W. (登録日: 2011-11-28, 公開日: 2012-08-22, 最終更新日: 2024-10-09)

主引用文献

Delfosse, V.,Grimaldi, M.,Pons, J.L.,Boulahtouf, A.,le Maire, A.,Cavailles, V.,Labesse, G.,Bourguet, W.,Balaguer, P.
Structural and mechanistic insights into bisphenols action provide guidelines for risk assessment and discovery of bisphenol A substitutes.
Proc.Natl.Acad.Sci.USA, 109:14930-14935, 2012

PubMed Abstract: Bisphenol A (BPA) is an industrial compound and a well known endocrine-disrupting chemical with estrogenic activity. The widespread exposure of individuals to BPA is suspected to affect a variety of physiological functions, including reproduction, development, and metabolism. Here we report that the mechanisms by which BPA and two congeners, bisphenol AF and bisphenol C (BPC), bind to and activate estrogen receptors (ER) α and β differ from that used by 17β-estradiol. We show that bisphenols act as partial agonists of ERs by activating the N-terminal activation function 1 regardless of their effect on the C-terminal activation function 2, which ranges from weak agonism (with BPA) to antagonism (with BPC). Crystallographic analysis of the interaction between bisphenols and ERs reveals two discrete binding modes, reflecting the different activities of compounds on ERs. BPA and 17β-estradiol bind to ERs in a similar fashion, whereas, with a phenol ring pointing toward the activation helix H12, the orientation of BPC accounts for the marked antagonist character of this compound. Based on structural data, we developed a protocol for in silico evaluation of the interaction between bisphenols and ERs or other members of the nuclear hormone receptor family, such as estrogen-related receptor γ and androgen receptor, which are two known main targets of bisphenols. Overall, this study provides a wealth of tools and information that could be used for the development of BPA substitutes devoid of nuclear hormone receptor-mediated activity and more generally for environmental risk assessment.

PubMed: 22927406
DOI: 10.1073/pnas.1203574109

実験手法

X-RAY DIFFRACTION (2.196 Å)