1UHL: Crystal structure of the LXRalfa-RXRbeta LBD heterodimer

Citation:
Abstract
The nuclear receptor heterodimers of liver X receptor (LXR) and retinoid X receptor (RXR) are key transcriptional regulators of genes involved in lipid homeostasis and inflammation. We report the crystal structure of the ligand-binding domains (LBDs) of LXRalpha and RXRbeta complexed to the synthetic LXR agonist T-0901317 and the RXR agonist methoprene acid (Protein Data Base entry 1UHL). Both LBDs are in agonist conformation with GRIP-1 peptides bound at the coactivator binding sites. T-0901317 occupies the center of the LXR ligand-binding pocket and its hydroxyl head group interacts with H421 and W443, residues identified by mutational analysis as critical for ligand-induced transcriptional activation by T-0901317 and various endogenous oxysterols. The topography of the pocket suggests a common anchoring of these oxysterols via their 22-, 24- or 27-hydroxyl group to H421 and W443. Polyunsaturated fatty acids act as LXR antagonists and an E267A mutation was found to enhance their transcriptional inhibition. The present structure provides a powerful tool for the design of novel modulators that can be used to characterize further the physiological functions of the LXR-RXR heterodimer.
PDB ID: 1UHLDownload
MMDB ID: 27976
PDB Deposition Date: 2003/7/3
Updated in MMDB: 2012/11
Experimental Method:
x-ray diffraction
Resolution: 2.9  Å
Source Organism:
Homo sapiens
Similar Structures:
Biological Unit for 1UHL: tetrameric; determined by author
Molecular Components in 1UHL
Label Count Molecule
Proteins (4 molecules)
1
Retinoic Acid Receptor Rxr-beta(Gene symbol: RXRB)
Molecule annotation
1
Oxysterols Receptor Lxr-alpha(Gene symbol: NR1H3)
Molecule annotation
2
10-mer Peptide From Nuclear Receptor Coactivator 2(Gene symbol: NCOA2)
Molecule annotation
Chemicals (2 molecules)
1
1
2
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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