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; p. 38821
• Main Authors: Mathias FärnegÃ¥rdh, Tomas Bonn, Sherry Sun, Jan Ljunggren, Harri Ahola, Anna Wilhelmsson, Jan-à ke Gustafsson, Mats Carlquist
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 03-10-2003
• 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.