The phantom ligand effect: Allosteric control of transcription by the retinoid X receptor

Abstract

Regulation of gene expression via allosteric control of transcription is one of the fundamental concepts of molecular biology. Studies in prokaryotes 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 changes can dramatically alter the DNA binding and/or trans-activation abilities of the target transcription factors. In this work, analysis of trans-activation by members of the steroid and thyroid hormone receptor superfamily identifies a unique form of allosteric control, the phantom ligand effect. Binding of a novel ligand (LG100754) to one subunit (RXR) of a heterodimeric transcription factor results in a linked conformational change in the second noncovalently bound subunit of the heterodimer (RAR). This conformational change results in both the dissociation of corepressors and association of coactivators in a fashion mediated by the activation function of the non-liganded subunit. Without occupying the RAR hormone binding pocket, binding of LG100754 to RXR mimics exactly the effects observed when hormone is bound to RAR. Thus, LG100754 behaves as a phantom ligand.