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.
Hassan
A Quamrul
AQ
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, USA.
Koh
John T
JT
D000494:Allosteric Regulation; D001665:Binding Sites; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011988:Receptors, Thyroid Hormone / Q000737:chemistry* / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014284:Triiodothyronine / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D008024:Ligands; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine