The retinoid X receptor (RXR) is a member of nuclear hormone receptor family proteins. RXR contains two signature domains of nuclear receptor family proteins, i.e. DNA-binding domain and ligand binding domain (LBD). RXR is a ligand-dependent transcription factor. The endogenous ligand for RXR is 9-cis retinoic acid. RXR plays an important role in many fundamental biological process such as reproduction, cellular differentiation, bone development, hematopoesis and pattern formation during embryogenesis (1). RXR is also implicated in some pathological conditions as neoplastic formation and it is a potential target for cancer therapy (2). More information on the basic of retinoic acid receptor and the implication in cancer therapy can be found at Dr.Matthieu Schapira's web site at New York University Medical School.
Vertebrate RXR includes at least three distinct genes (RXR alpha, beta and gamma) which give rise to a large number of protein products through differential promoter usage and alternative splicing. Besides acting as a homodimer, RXR plays a central role in regulating the activity of other nuclear hormone receptors by acting as a partner for heterodimers. RXR forms a functional heterodimer with retinoic acid receptor (RAR), thyroid hormone receptor, vitamin D receptor, NGFI-B and many other nuclear receptors. Different binding partner of RXR renders a different DNA-binding specificity of the heterodimer. The current model for ligand-dependent activation of nuclear receptors including RXR is focusing on the conformational transition between the ligand-free (apo) and ligand-occupied (holo) forms of the receptors. The apo form binds to DNA and recruits a large protein complex of corepressors, such as histone deacetylase, and actively represses the transcription of a target gene. Once the ligand is bound, the receptor in holo form undergoes a dramatic conformational changes and releases the corepressor complex. Simutaneously, the holo form of the receptor recruits a large complex of coactivator and actively acts as a transcriptional activator (3). The similar events are applied to the activation of other ligand-gated nuclear receptor as well. Learn more on the comparative studies of the apo and holo form of retinoic acid receptor at the Theoretical Biophysics Group at the University of Illinoi at Urbana Champange.
Since the ligand binding domain of RXR is the site where corepressor or coactivator complexes bind to, it is speculated to be the major site of conformational changes upon ligand binding. The crystal structures of the apo and holo forms of RXR have been resolved by X-ray crystallography (4,5). The aim of this presentation is to explore the basic structure of the human RXR alpha ligand binding domain, the binding site for the ligand and the cnformational changes upon ligand binding.
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