title: The three-dimensional structure of the liver X receptor beta reveals a flexible ligand-binding pocket that can accommodate fundamentally different ligands.
abstract: The structures of the liver X receptor LXRbeta (NR1H2) have been determined in complexes with two synthetic ligands, T0901317 and GW3965, to 2.1 and 2.4 A, respectively. Together with its isoform LXRalpha (NR1H3) it regulates target genes involved in metabolism and transport of cholesterol and fatty acids. The two LXRbeta structures reveal a flexible ligand-binding pocket that can adjust to accommodate fundamentally different ligands. The ligand-binding pocket is hydrophobic but with polar or charged residues at the two ends of the cavity. T0901317 takes advantage of this by binding to His-435 close to H12 while GW3965 orients itself with its charged group in the opposite direction. Both ligands induce a fixed "agonist conformation" of helix H12 (also called the AF-2 domain), resulting in a transcriptionally active receptor.
authors.affiliation: Karo Bio AB, NOVUM, Karolinska Institute, Huddinge University Hosptial, Sweden. mathias.farnegardh@karobio.se
authors.forename: Mathias
authors.initials: M
authors.lastname: Färnegårdh
authors.forename: Tomas
authors.initials: T
authors.lastname: Bonn
authors.forename: Sherry
authors.initials: S
authors.lastname: Sun
authors.forename: Jan
authors.initials: J
authors.lastname: Ljunggren
authors.forename: Harri
authors.initials: H
authors.lastname: Ahola
authors.forename: Anna
authors.initials: A
authors.lastname: Wilhelmsson
authors.forename: Jan-Ake
authors.initials: JA
authors.lastname: Gustafsson
authors.forename: Mats
authors.initials: M
authors.lastname: Carlquist
mesh_terms: D000409:Alanine / Q000737:chemistry; D001665:Binding Sites; D002784:Cholesterol / Q000378:metabolism; D004268:DNA-Binding Proteins; D019281:Dimerization; D004583:Electrons; D004926:Escherichia coli / Q000378:metabolism; D006639:Histidine / Q000737:chemistry; D006801:Humans; D008024:Ligands; D000071518:Liver X Receptors; D008956:Models, Chemical; D008958:Models, Molecular; D015233:Models, Statistical; D057093:Orphan Nuclear Receptors; D011485:Protein Binding; D011487:Protein Conformation; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014965:X-Rays
chemical_list: D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; C000605210:NR1H2 protein, human; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D006639:Histidine; D002784:Cholesterol; D000409:Alanine