Crystal structure of the pregnane X receptor-estradiol complex provides insights into endobiotic recognition.
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Xue Y, Moore LB, Orans J, Peng L, Bencharit S, Kliewer SA, Redinbo MR
Crystal structure of the pregnane X receptor-estradiol complex provides insights into endobiotic recognition.
Mol Endocrinol. 2007 May;21(5):1028-38. Epub 2007 Feb 27.
- PubMed ID
- 17327420 [ View in PubMed]
- Abstract
The human nuclear pregnane X receptor (PXR) responds to a wide variety of xenobiotic and endobiotic compounds, including pregnanes, progesterones, corticosterones, lithocholic acids, and 17beta-estradiol. In response to these ligands, the receptor controls the expression of genes central to the metabolism and excretion of potentially harmful chemicals from both exogenous and endogenous sources. Although the structural basis of PXR's interaction with small and large xenobiotics has been examined, the detailed nature of its binding to endobiotics, including steroid-like ligands, remains unclear. We report the crystal structure of the human PXR ligand-binding domain (LBD) in complex with 17beta-estradiol, a representative steroid ligand, at 2.65 A resolution. Estradiol is found to occupy only one region of PXR's expansive ligand-binding pocket, leaving a notable 1000 A3 of space unoccupied, and to bridge between the key polar residues Ser-247 and Arg-410 in the PXR LBD. Positioning the steroid scaffold in this way allows it to make several direct contacts to alphaAF of the receptor's AF-2 region. The PXR-estradiol complex was compared with that of other nuclear receptors, including the estrogen receptor, in complexes with analogous ligands. It was found that PXR's placement of the steroid is remarkably distinct relative to other members of the nuclear receptor superfamily. Using the PXR-estradiol complex as a guide, the binding of other steroid- and cholesterol-like molecules was then considered. The results provide detailed insights into the manner in which human PXR responds to a wide range of endobiotic compounds.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Estradiol Nuclear receptor subfamily 1 group I member 2 Protein Humans UnknownBinderDetails Estradiol acetate Nuclear receptor subfamily 1 group I member 2 Protein Humans UnknownNot Available Details Estradiol benzoate Nuclear receptor subfamily 1 group I member 2 Protein Humans UnknownNot Available Details Estradiol cypionate Nuclear receptor subfamily 1 group I member 2 Protein Humans UnknownNot Available Details Estradiol dienanthate Nuclear receptor subfamily 1 group I member 2 Protein Humans UnknownNot Available Details Estradiol valerate Nuclear receptor subfamily 1 group I member 2 Protein Humans UnknownNot Available Details Ethinylestradiol Nuclear receptor subfamily 1 group I member 2 Protein Humans UnknownAgonistDetails