4X1G
Crystal structure of the hPXR-LBD in complex with the synthetic estrogen 17alpha-ethinylestradiol and the pesticide trans-nonachlor
Summary for 4X1G
| Entry DOI | 10.2210/pdb4x1g/pdb |
| Related | 4X1F |
| Descriptor | Nuclear receptor subfamily 1 group I member 2, Ethinyl estradiol, Trans-nonachlor, ... (6 entities in total) |
| Functional Keywords | hormone receptor, estrogen, pesticide, gene regulation |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 37199.76 |
| Authors | Delfosse, V.,Huet, T.,Bourguet, W. (deposition date: 2014-11-24, release date: 2015-09-09, Last modification date: 2024-01-10) |
| Primary citation | 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 Cited by 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: 26333997DOI: 10.1038/ncomms9089 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.25 Å) |
Structure validation
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