Since ABC transporters recognize and export a range of chemicals, it makes sense to implement strategies to regulate their overexpression. Overexpression of efflux pumps is controlled by transcriptional regulators of the PDR network Pdr1p and Pdr3p. Pdr1p/Pdr3p regulate expression of certain PDR exporters by binding to consensus motifs called pleiotropic drug-resistance elements (PDREs). Homologous PDR pathways have been identified in other species, such as Canadida albicans and Aspergillus fumigatus. These regulators form dimers and work in concert by recognizing a series of CGG repeats in the promoter region of target genes.
Interestingly, these transcriptional regulators can tolerate sequence variation in the binding site and also recognize degenerate PDRE sites, but how these differences are used in the regulatory process have yet to be explored. Additionally, Pdr1p and Pdr3p can recognize multiple PDRE sites within a single promoter. Pdr1p in S. cerevisiae and C. glabrata directly bind the same xenobiotics to activate genes encoding PDR transporters. The effects of xenobiotic binding on affinity and specificity have yet to be explored.
Differences in the PDRE motifs and in the DNA-binding domain of Pdr1p and Pdr3p must allow for differential regulation, making this a unique system for investigation and a possible drug target.
We are interested in two areas which we will address using genetic studies, x-ray crystallography and single molecule experiments:
Is PDR is controlled by differences in the DNA-binding domains of Pdr1p and Pdr3p, coupled with variability in the PDRE sites in the promoter region?
It is possible that the presence of xenobiotics modified DNA binding and in turn impacts the expression of PDR transporters?