A functionally orthogonal ligand-receptor pair created by targeting the allosteric mechanism of the thyroid hormone receptor.

Nuclear receptors are ligand-dependent transcription factors that are of interest as potential tools to artificially regulate gene expression. Ligand binding induces a conformational change involving helix-12 which forms part of the dimerization interface used to bind transcriptional coactivators. When triiodothyronine (T3) binds the thyroid hormone receptor (TR) it indirectly contacts helix-12 through intermediary residues His(435) and Phe(451) termed a His-Phe switch. The mutant TRbeta(H435A) is nonresponsive to physiological concentrations of T3 but can be activated by the synthetic hormone analogue QH2 which potently activates His435-->Ala mutant at concentrations that do not activate the wild-type receptors TRalpha and TRbeta. QH2 does not show antagonist behavior with the wild-type TRs. QH2's functionally orthogonal behavior with TRbeta(H435A) is preserved on the three consensus thyroid hormone response elements.