THE PHANTOM LIGAND EFFECT - ALLOSTERIC CONTROL OF TRANSCRIPTION BY THE RETINOID-X RECEPTOR

Regulation of gene expression via allosteric control of transcription is one of the fundamental concepts of molecular biology. Studies in pr okaryotes have illustrated that binding of small molecules or ligands to sequence-specific transcription factors can produce conformational changes at a distance from the binding site. These ligand-induced chan ges can dramatically alter the DNA binding and/or trans-activation abi lities of the target transcription factors. In this work, analysis of trans-activation by members of the steroid and thyroid hormone recepto r superfamily identifies a unique form of allosteric control, the phan tom ligand effect. Binding of a novel ligand (LG100754) to one submit (RXR) of a heterodimeric transcription factor results in a linked conf ormational change in the second noncovalently bound subunit of the het erodimer (RAR). This conformational change results in both the dissoci ation of corepressors and association of coactivators in a fashion med iated by the activation function of the non-liganded subunit. Without occupying the RAR hormone binding pocket, binding of LG100754 to RXR m imics exactly the effects observed when hormone is bound to RAR. Thus, L6100754 behaves as a phantom ligand.