Figure 5.

Conventional and unconventional modes of nuclear receptor action. Comparison of the modes of action used by nuclear receptors for transcriptional activation and repression. In the conventional mode, agonist binding positions the helix H12 (shown in orange) to an active site that favors the coactivator binding. Antagonist binding dislodges H12 from the active site and opens up an extended groove to promote the corepressor binding. In the unconventional mode, the orphan nuclear receptor SHP lacks the traditional helix H1, which leads to an H1 pocket to recruit the corepressor EID1 that is otherwise covered by H1. The orphan nuclear receptor TLX uses another pocket underneath helix H12 to recruit the corepressor Atrophin, which is consistent with its autorepressed conformation. It is possible that both repressive modes are present in the same one of several ligand-free orphan nuclear receptors, considering they share similar structural features, including lack of H1 and an autorepressed conformation. Representative structures from left to right show PPARγ/SRC1 (PDB code 1FM6), PPARα/SMRT (PDB code 1KKQ), SHP/EID1 (PDB code 4NUF), and TLX/Atrophin (PDB code in this study). X indicates any amino acid. The EID1 residues that mediate the SHP interaction are underlined.