Development of artificial nuclear receptors, the synthetic yeast approach

The field of synthetic biology has demonstrated to be a valuable tool in research as well as in medical and industrial applications. Nowadays, it’s not only possible to replace an organism’s genetic material with synthetic DNA but also to engineer the function of that synthetic DNA and establish genetic circuits that respond to either external or internal stimuli. A well-characterized orthogonal sensing system is the ON-switch, which induces target gene expression upon ligand binding. Optimal ON-switches for yeasts and plants are the nuclear receptors which aren’t naturally expressed in these organisms. Given the highly modular nature of nuclear receptors, the ability of the nuclear receptors to adapt to a completely different ligand only requires the redesign of its ligand binding domain. By modifying the ligand binding domain of nuclear receptors to adapt to a ligand of our choice we want to establish an artificial ON-switch in yeast. However, synthetic biology is currently limited to natural occurring protein building blocks, while specialized building blocks are required to convert binding of synthetic ligands into biochemical effects. Therefore, we will employ methods of computational protein design and directed evolution to overcome the current limitations and realize a novel biosensor that is safe for the organism and the environment. This novel nuclear receptor based biosensor will have a great impact because of its wide range of applications as an orthogonal signaling system in yeast or plants or as a new, more specific version of an inducible Cre for the Cre-Lox system in mammalians. Any progress leads to years of further developmental research.