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  • The EMBO Journal (2003) 22, 4625 - 4633
  • doi:10.1093/emboj/cdg456

Crystal structure of the heterodimeric complex of LXRalpha and RXRbold beta ligand-binding domains in a fully agonistic conformation

Stefan Svensson1, Tove Östberg2, Micael Jacobsson1,3, Carina Norström1, Karin Stefansson1, Dan Hallén1, Isabel Climent Johansson4, Kristina Zachrisson1, Derek Ogg1 and Lena Jendeberg4

  1. Department of Structural Chemistry Biovitrum AB, Lindhagensgatan 133, SE-112 76 Stockholm, Sweden
  2. Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, SE-171 77 Stockholm, Sweden
  3. Department of Medicinal Chemistry, Uppsala University, SE-751 23 Uppsala, Sweden
  4. Department of Biology, Biovitrum AB, Lindhagensgatan 133, SE-112 76 Stockholm, Sweden

Correspondence to:

Stefan Svensson, E-mail: stefan.j.svensson@biovitrum.com

Received 10 April 2003; Accepted 23 July 2003; Revised 8 July 2003

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.

  • Keywords:

    • crystal structure,
    • lipid metabolism,
    • mutational analysis,
    • nuclear receptor,
    • transcription