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The Nuclear Receptor Field: A Historical Overview and Future Challenges

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The Nuclear Receptor Field: A Historical Overview and Future Challenges

Gisela I Mazaira et al. Nucl Receptor Res.

Abstract

In this article we summarize the birth of the field of nuclear receptors, the discovery of untransformed and transformed isoforms of ligand-binding macromolecules, the discovery of the three-domain structure of the receptors, and the properties of the Hsp90-based heterocomplex responsible for the overall structure of the oligomeric receptor and many aspects of the biological effects. The discovery and properties of the subfamily of receptors called orphan receptors is also outlined. Novel molecular aspects of the mechanism of action of nuclear receptors and challenges to resolve in the near future are discussed.

Keywords: Chaperones; Heat-shock proteins; Hsp90; Nuclear receptor; Steroid receptor; Transcriptional regulation.

Conflict of interest statement

Competing Interests The authors declare no competing interests.

Figures

Figure 1:
Figure 1:. Domain structure of nuclear receptors (A-F).
The DNA binding domain (DBD) or C region consists of two zinc-binding motifs (or Zn-fingers), that often includes a hinge domain or D region. A nuclear localization signal 1 (NL1) is usually located at the C-terminal end of this region. The ligand binding domain (LBD) or E/F region binds the cognate ligand. Ligands of the orphan receptor subfamily are not known, and it is thought that they could be endogenous compounds, possibly metabolic intermediates, or even environmental factors, which may explain some of their apparently constitutive transactivation activity and the difficulty encountered to identify their ligands. The AF1 and AF2 activation function 1 and 2 contact co-regulatory molecules, but AF-1 is typically a variable ligand-independent (first named transactivation domain. TD) while the AF-2 of the E/F region is ligand-dependent.
Figure 2:
Figure 2:. Evolutionary tree of the nuclear receptor family.
The tree branches of the scheme show nodes well supported at bootstrap values >90%. Roman numbers group each subfamily of the superfamily. Note that the consensus phylogenetic position of the nuclear receptors is not correlated with the chemical nature of the cognate ligand.
Figure 3:
Figure 3:. Endogenous and xenobiotic lipophilic ligands.
Various xenobiotics and endogenous lipids are able to activate several nuclear receptors, which in turn control have the physiological role of controlling the intrahepatic and extrahepatic levels of these compounds. Thus, these receptors regulate the metabolism and excretion of these compounds. Note that a relatively high redundancy exists for several substance classes to bind to multiple receptors.

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