The three-dimensional structure of the liver X receptor β reveals a flexible ligand-binding pocket that can accommodate fundamentally different ligands

Mathias Färnegårdh, Tomas Bonn, Sherry Sun, Jan Ljunggren, Harri Ahola, Anna Wilhelmsson, Jan Åke Gustafsson, Mats Carlquist

Research output: Contribution to journalArticle

130 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)38821-38828
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number40
DOIs
StatePublished - Oct 3 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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