4X1G

Crystal structure of the hPXR-LBD in complex with the synthetic estrogen 17alpha-ethinylestradiol and the pesticide trans-nonachlor

4X1G の概要

• エントリーDOI: 10.2210/pdb4x1g/pdb
• 関連するPDBエントリー: 4X1F
• 分子名称: Nuclear receptor subfamily 1 group I member 2, Ethinyl estradiol, Trans-nonachlor, ... (6 entities in total)
• 機能のキーワード: hormone receptor, estrogen, pesticide, gene regulation
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37199.76

構造登録者

Delfosse, V.,Huet, T.,Bourguet, W. (登録日: 2014-11-24, 公開日: 2015-09-09, 最終更新日: 2024-01-10)

主引用文献

Delfosse, V.,Dendele, B.,Huet, T.,Grimaldi, M.,Boulahtouf, A.,Gerbal-Chaloin, S.,Beucher, B.,Roecklin, D.,Muller, C.,Rahmani, R.,Cavailles, V.,Daujat-Chavanieu, M.,Vivat, V.,Pascussi, J.M.,Balaguer, P.,Bourguet, W.
Synergistic activation of human pregnane X receptor by binary cocktails of pharmaceutical and environmental compounds.
Nat Commun, 6:8089-8089, 2015

PubMed Abstract: Humans are chronically exposed to multiple exogenous substances, including environmental pollutants, drugs and dietary components. Many of these compounds are suspected to impact human health, and their combination in complex mixtures could exacerbate their harmful effects. Here we demonstrate that a pharmaceutical oestrogen and a persistent organochlorine pesticide, both exhibiting low efficacy when studied separately, cooperatively bind to the pregnane X receptor, leading to synergistic activation. Biophysical analysis shows that each ligand enhances the binding affinity of the other, so the binary mixture induces a substantial biological response at doses at which each chemical individually is inactive. High-resolution crystal structures reveal the structural basis for the observed cooperativity. Our results suggest that the formation of 'supramolecular ligands' within the ligand-binding pocket of nuclear receptors contributes to the synergistic toxic effect of chemical mixtures, which may have broad implications for the fields of endocrine disruption, toxicology and chemical risk assessment.

PubMed: 26333997
DOI: 10.1038/ncomms9089

実験手法

X-RAY DIFFRACTION (2.25 Å)