PDBsum entry 4x1f

Gene regulation

PDB id: 4x1f

Contents

Protein chain

271 a.a.

Ligands

3WF

MPD ×2

Waters ×170

PDB id:

4x1f

Name:

Gene regulation

Title:

Crystal structure of the hpxr-lbd in complex with the synthetic estrogen 17alpha-ethinylestradiol

Structure:

Nuclear receptor subfamily 1 group i member 2. Chain: a. Fragment: unp residues 130-434. Synonym: orphan nuclear receptor par1,orphan nuclear receptor pxr, pregnane x receptor,steroid and xenobiotic receptor,sxr. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: nr1i2, pxr. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.00Å R-factor: 0.184 R-free: 0.210

Authors:

V.Delfosse,T.Huet,W.Bourguet

Key ref:

V.Delfosse et al. (2015). Synergistic activation of human pregnane X receptor by binary cocktails of pharmaceutical and environmental compounds. Nat Commun, 6, 8089. PubMed id: 26333997 DOI: 10.1038/ncomms9089

Date:

24-Nov-14 Release date: 09-Sep-15

Protein chain

O75469  (NR1I2_HUMAN) -  Nuclear receptor subfamily 1 group I member 2 from Homo sapiens

Seq: 434 a.a.

Struc: 271 a.a.

DOI no: 10.1038/ncomms9089

Nat Commun 6:8089 (2015)

PubMed id: 26333997

Synergistic activation of human pregnane X receptor by binary cocktails of pharmaceutical and environmental compounds.

V.Delfosse, B.Dendele, T.Huet, M.Grimaldi, A.Boulahtouf, S.Gerbal-Chaloin, B.Beucher, D.Roecklin, C.Muller, R.Rahmani, V.Cavaillès, M.Daujat-Chavanieu, V.Vivat, J.M.Pascussi, P.Balaguer, W.Bourguet.

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.