(326e) Analysis of the Roles of Mutations in Nuclear Hormone Receptors in a Bacterial Biosensor System

Mutations in nuclear hormone receptors (NHRs) usually lead to metabolic disorders, but are difficult to treat with existing drugs due to the aberrant behavior of the receptor.  In our previous work, we created several hormone biosensors based on bacterial growth phenotypes, which allow hormone detection in both human and animal hormone receptors. In this study, we introduced six clinically relevant human mutations into our thyroid hormone receptor-β and peroxisome proliferator-activated receptor-γ sensor.  For each group of mutated biosensors, several native and mimic ligands were tested.  Compared to their respective wild-type native sensor, we found that these six mutations have varying effects on ligand binding.  More specifically, some mutations lead to partial loss of ligand binding ability, while some fully disable ligand binding ability.  These mutant biosensors can be thus used to efficiently screen for effective drug candidates to treat human patients that harbor these rare mutations.