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.
Hoerer
Stefan
S
Department of Lead Discovery, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, D-88397 Biberach/Riss, Germany.
Schmid
Angela
A
Heckel
Armin
A
Budzinski
Ralph M
RM
Nar
Herbert
H
D000595:Amino Acid Sequence; D000924:Anticholesteremic Agents / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D000071518:Liver X Receptors; D008958:Models, Molecular; D008969:Molecular Sequence Data; D057093:Orphan Nuclear Receptors; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism; D013449:Sulfonamides; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000924:Anticholesteremic Agents; D002784:Cholesterol; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides