1UPV: Crystal structure of the human Liver X receptor beta ligand binding domain in complex with a synthetic agonist

LXRbeta belongs to the nuclear hormone receptor superfamily of ligand-activated transcription factors. Its natural ligands are supposed to be oxidised derivatives of cholesterol. Stimulation of LXRbeta by agonists activates a number of genes that are involved in the regulation of lipid metabolism and cholesterol efflux from cells. Therefore, LXRbeta may represent a novel therapeutic target for the treatment of dyslipidemia and atherosclerosis.Here, we report the X-ray crystal structure of the LXRbeta ligand-binding domain in complex with a synthetic agonist, T-0901317. This compound occupies the ligand-binding pocket of the receptor, forms numerous lipophilic contacts with the protein and one crucial hydrogen bond to His435 and stabilises the agonist conformation of the receptor ligand-binding domain. The recruitment of the AF2-region of the protein is not achieved via direct polar interactions of the ligand with protein side-chains of this helical segment, but rather via few hydrophobic contacts and probably more importantly via indirect effects involving the pre-orientation of side-chains that surround the ligand-binding pocket and form the interface to the AF2-helix. On the basis of these results we propose a binding mode and a mechanism of action for the putative natural ligands, oxidised derivatives of cholesterol.
PDB ID: 1UPVDownload
MMDB ID: 30042
PDB Deposition Date: 2003/10/13
Updated in MMDB: 2004/12
Experimental Method:
x-ray diffraction
Resolution: 2.1  Å
Source Organism:
Similar Structures:
Biological Unit for 1UPV: monomeric; determined by author and by software (PQS)
Molecular Components in 1UPV
Label Count Molecule
Protein (1 molecule)
Oxysterols Receptor Lxr-beta(Gene symbol: NR1H2)
Molecule annotation
Chemical (1 molecule)
* Click molecule labels to explore molecular sequence information.

Citing MMDB