Crystal structure of the pregnane X receptor-estradiol complex provides insights into endobiotic recognition.

Crystal structure of the pregnane X receptor-estradiol complex provides insights into endobiotic recognition. Research Abstract Details 

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Crystal structure of the pregnane X receptor-estradiol complex provides insights into endobiotic recognition. Abstract Text:

Yu Xue,Linda B Moore,Jillian Orans,Li Peng,Sompop Bencharit,Steven A Kliewer,Matthew R Redinbo,

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.

Crystal structure of the pregnane X receptor-estradiol complex provides insights into endobiotic recognition. Publishing Authors By Initials

Y Xue,LB Moore,J Orans,L Peng,S Bencharit,SA Kliewer,MR Redinbo,

For similar proteins: receptors, cytoplasmic and nuclear: receptors, steroid research abstracts see: proteins: receptors, cytoplasmic and nuclear: receptors, steroid research

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MEDLINE DATE:

Crystal structure of the pregnane X receptor-estradiol complex provides insights into endobiotic recognition. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Molecular endocrinology (Baltimore, Md.)

VOLUME: 21

Page Numbers: 1028-38

Journal Abbreviation:

ISSN: 0888-8809

DAY: 27

MONTH: 02

YEAR: 2007

Crystal structure of the pregnane X receptor-estradiol complex provides insights into endobiotic recognition. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 8801431

Crystal structure of the pregnane X receptor-estradiol complex provides insights into endobiotic recognition. Keywords Mesh Terms:

KEYWORDS: Receptors, Steroid

MESH TERMS: metabolism

Chemical & Substance for Abstract: Crystal structure of the pregnane X receptor-estradiol complex provides insights into endobiotic recognition. Information

Substance Name: Estradiol

Registry Number: 50-28-2

Grant and Affiliation Information for Crystal structure of the pregnane X receptor-estradiol complex provides insights into endobiotic recognition.

AFFILIATION: Department of Chemistry, CB 3290, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, USA.

Country: United States

AGENCY: United States NIDDK

GRANT: DK62229

ACRONYM: DK

MEDLINETA: Mol Endocrinol

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