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.