The Three-dimensional Structure of the Liver X Receptor β Reveals a Flexible Ligand-binding Pocket That Can Accommodate Fundamentally Different Ligands

• Published in: The Journal of biological chemistry Vol. 278; no. 40; pp. 38821 - 38828
• Main Authors: Färnegårdh, Mathias, Bonn, Tomas, Sun, Sherry, Ljunggren, Jan, Ahola, Harri, Wilhelmsson, Anna, Gustafsson, Jan-Åke, Carlquist, Mats
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03-10-2003
• Subjects: Alanine - chemistry; Binding Sites; Cholesterol - metabolism; Dimerization; DNA-Binding Proteins; Electrons; Escherichia coli - metabolism; Histidine - chemistry; Humans; Ligands; Liver X Receptors; Medicin och hälsovetenskap; Models, Chemical; Models, Molecular; Models, Statistical; Orphan Nuclear Receptors; Protein Binding; Protein Conformation; Protein Isoforms; Protein Structure, Tertiary; Receptors, Cytoplasmic and Nuclear - chemistry; Receptors, Cytoplasmic and Nuclear - metabolism; Transcription Factors - metabolism; Transcription, Genetic; X-Rays
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M304842200

The structures of the liver X receptor LXRβ (NR1H2) have been determined in complexes with two synthetic ligands, T0901317 and GW3965, to 2.1 and 2.4 Å, respectively. Together with its isoform LXRα (NR1H3) it regulates target genes involved in metabolism and transport of cholesterol and fatty acids. The two LXRβ 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.