Abstract
Chemical complementation (CC), a three‐component genetic selection system, links the presence of a small molecule to the survival of yeast through the action of a nuclear receptor (NR). CC is used to engineer receptors to activate transcription by a desired small molecule. The retinoid X receptor (RXR) is the only NR used in CC to date. PXR is an attractive NR to use in CC because it is a promiscuous receptor that activates transcription through a variety of ligands (including rifampicin and 17‐β‐estradiol). We expressed PXR in the CC system and found it is constitutively active (i.e. the yeast grow in the absence of an exogenously applied ligand) making PXR unfit for use in CC. To make PXR suitable for use, we are taking several approaches. We have engineered a yeast strain with the ERG24 steroid biosynthetic gene knocked out to remove potential endogenous sterol ligands. We are also testing PXR in mammalian cells to understand the possible mechanism of PXR function through analysis with RXR. We are investigating RXR/PXR heterodimer and PXR/PXR homodimer activation to determine the role of RXR heterodimerization in PXR activity, as well as the role of co‐repressor proteins. Funding provided by NIH.
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