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Structural analysis of nuclear recep...

Devarakonda, Srikripa.

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Structural analysis of nuclear receptor interaction complexes.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Structural analysis of nuclear receptor interaction complexes./
Author:	Devarakonda, Srikripa.
Description:	155 p.
Notes:	Source: Dissertation Abstracts International, Volume: 64-10, Section: B, page: 4817.
Contained By:	Dissertation Abstracts International64-10B.
Subject:	Biophysics, General. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3108775

Structural analysis of nuclear receptor interaction complexes.
Devarakonda, Srikripa.

Structural analysis of nuclear receptor interaction complexes. - 155 p.

Source: Dissertation Abstracts International, Volume: 64-10, Section: B, page: 4817.

Thesis (Ph.D.)--University of Virginia, 2004.

Nuclear receptors are a superfamily of ligand-activated transcription factors that mediate growth, development and physiology in a variety of eukaryotes. Two domains define their functionality---DNA binding domain (DBD) and ligand-binding domain (LBD). This dissertation provides a structural analysis of receptor-DNA interactions for the oxysterol receptor LXR and Drosophila ecdysone receptor, EcR and receptor-ligand interactions for the bile acid receptor, FXR.Subjects--Topical Terms:

1019105
Biophysics, General.

Structural analysis of nuclear receptor interaction complexes.
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035 $a (UnM)AAI3108775
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100 1 $a Devarakonda, Srikripa. $3 1952434
245 1 0 $a Structural analysis of nuclear receptor interaction complexes.
300 $a 155 p.
500 $a Source: Dissertation Abstracts International, Volume: 64-10, Section: B, page: 4817.
500 $a Adviser: Fraydoon Rastinejad.
502 $a Thesis (Ph.D.)--University of Virginia, 2004.
520 $a Nuclear receptors are a superfamily of ligand-activated transcription factors that mediate growth, development and physiology in a variety of eukaryotes. Two domains define their functionality---DNA binding domain (DBD) and ligand-binding domain (LBD). This dissertation provides a structural analysis of receptor-DNA interactions for the oxysterol receptor LXR and Drosophila ecdysone receptor, EcR and receptor-ligand interactions for the bile acid receptor, FXR.
520 $a As a sensor for whole body cholesterol, LXR transcriptionally regulates genes involved in cholesterol homeostasis. LXR recognizes response elements resembling direct repeats of the 5'-AGGTCA-3' motif separated by four base-pairs, as a heterodimer with RXR. Crystals of the DBD-DNA complex diffracted poorly and gel-shift assays demonstrated that the DBDs alone were not capable of forming a high-affinity dimer on DNA.
520 $a EcR functions as a heterodimer with Ultraspiracle (USP, the Drosophila homolog of RXR) and is responsible for initiating metamorphosis in insects. The EcR-USP heterodimer mediates transcription through degenerate response elements, resembling inverted repeats of the consensus motif separated by one base-pair. A 2.24 A crystal structure of the EcR-USP-DBD heterodimer and a 2.60 A structure of the EcR-RXR heterodimer, bound to an idealized IR-1 element are described. EcR and USP use similar surfaces within their DBDs, and rely on the deformed minor groove of the DNA spacer to establish their contacts. Furthermore, dimerization and DNA-binding interfaces are preserved in the two complexes. These structures indicate how receptor heterodimers take advantage of adaptable protein and DNA surfaces to form pseudo-symmetric complexes on inverted repeats. Additionally, sequence alignments indicate that the EcR-RXR heterodimer is an important model for understanding how the FXR-RXR heterodimer binds to IR-1 sites.
520 $a FXR is responsible for regulating bile acid homeostasis in the liver and intestine. Crystal structures of the FXR-LBD in complex with two bile acids and coactivator peptide were solved. The structures reveal that FXR utilizes unique amphipathic and physiochemical characteristics of bile acids for ligand discrimination. Activation of FXR by bile acids involves a cation-pi switch resulting in the association of coactivator peptide with the activated LBD. These structures provide insights into design of therapeutic bile acids for treatment of hyperlipidemia and cholestasis.
590 $a School code: 0246.
650 4 $a Biophysics, General. $3 1019105
690 $a 0786
710 2 0 $a University of Virginia. $3 645578
773 0 $t Dissertation Abstracts International $g 64-10B.
790 1 0 $a Rastinejad, Fraydoon, $e advisor
790 $a 0246
791 $a Ph.D.
792 $a 2004
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3108775