Crystal structure of the heterodimeric complex of LXRalpha and RXRbeta ligand-binding domains in a fully agonistic conformation.
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.
Svensson
Stefan
S
Department of Structural Chemistry, Biovitrum AB, Lindhagensgatan 133, SE-112 76 Stockholm, Sweden. stefan.j.svensson@biovitrum.com
Ostberg
Tove
T
Jacobsson
Micael
M
Norström
Carina
C
Stefansson
Karin
K
Hallén
Dan
D
Johansson
Isabel Climent
IC
Zachrisson
Kristina
K
Ogg
Derek
D
Jendeberg
Lena
L
D001483:Base Sequence; D001665:Binding Sites; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000737:chemistry*; D019281:Dimerization; D004926:Escherichia coli / Q000235:genetics; D008024:Ligands; D000071518:Liver X Receptors; D008958:Models, Molecular; D057093:Orphan Nuclear Receptors; D010446:Peptide Fragments / Q000737:chemistry; D016133:Polymerase Chain Reaction; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry
D017931:DNA Primers; D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010446:Peptide Fragments; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins