Retinoic X receptor (RXR) is a master nuclear receptor in the processes of cell development and homeostasis, and is considered as an important target for the treatment of cancer and metabolic diseases. Unliganded RXR exists in an auto-repressed tetramer, and agonists can induce RXR dimerization and coactivator recruitment for activation. However, the molecular mechanisms involving the corepressor recruitment and antagonist-mediated repression of RXR are still elusive.
The repressive mechanism of RXR and the crystal structure of RXR-antagonist were firstly revealed by Xu Shen’s group in Shanghai Institute of Materia Medica (J Biol Chem. 2011, 286(3):1868-75). Further research on RXR repression is now achieved by corporation of Xu Shen and Hualiang Jiang’s groups (J. Biol. Chem. May 24, 2011, doi:10.1074/jbc.M111.245498).
Here they report the crystal structure of RXRa ligand-binding domain (LBD) complexed with silencing mediator for retinoid and thyroid hormone receptors (SMRT) corepressor motif. As the first structural report on the unliganded nuclear receptor bound to the corepressor motif, RXRaLBD–SMRT exhibits a significant structural rearrangement, compared with apo RXRaLBD tetramer. To further elucidate the molecular determinants for RXR repression by its antagonist, they also determine the crystal structure of RXRaLBD-SMRT complexed with the identified antagonist rhein. In the structure, two rhein molecules and two SMRT peptides are in the RXRaLBD tetramer, different from the case in RXRαLBD-SMRT structure, where four SMRT peptides bind to RXRαLBD tetramer. It seems that rhein induces a displacement of SMRT motif by activation function-2 (AF-2) motif binding to the receptor. Combining their current work with the published results, structural superposition of RXRaLBDs in different states reveals that RXR uses an overlapped binding site for coactivator, corepressor and AF-2 motifs, while AF-2 motif adopts different conformations for agonist or antagonist interaction, and coactivator or corepressor recruitment. Taken together, they thus propose a molecular model of RXR repression on the tetramer. Their results are expected to provide a new strategy for the drug design targeting RXR and insights into the pathology of RXR-involved cancer and metabolic diseases.
This work was achieved by PhD student Haitao Zhang, and supported by grants from National Natural Science Foundation of China and Shanghai Science and Technology Commission.