Our Work

G protein-coupled receptors (GPCRs) dominate the therapeutic market as the targets for more than 30 percent of FDA-approved drugs. They also recognize most drugs of abuse, including opioids, cannabinoids, LSD, cocaine and methamphetamine. Unlike many signaling proteins that function as binary switches between "on and off" states, GPCRs feature a ligand-independent basal activity that is increased or decreased upon orthosteric ligand binding and then further regulated by allosteric modulators. A single receptor may specifically recognize several ligands and respond uniquely to each, creating a complex conformational landscape. There is immense therapeutic potential in the ability to tune receptor signaling using partial agonists, biased agonists or allosteric modulators, and it remains poorly understood and virtually untapped.

The long-term vision of the Ziarek Lab is to decipher the molecular mechanisms of GPCR allostery for rational drug discovery. The lab's current understanding of biased agonism derives primarily from cell-based functional assays that are easily complicated by receptor expression levels, off-target effects and cell type. Integrating biophysical studies of purified protein with this cellular information would permit a complete molecular understanding. Some research areas the Ziarek Lab is currently making progress on are:

1. Investigating the conformational space of wildtype GPCRs using a combined biophysical and computational approach
2. Characterizing the allosteric mechanisms of arrestin activation
3. Developing novel ¹⁹F-NMR labels, pulse programs and NMR data analysis pipelines for expanding the molecular weight limits of NMR
4. Testing if arrestin’s local disorder and conformational entropy play a role in receptor and scaffolding function
5. Actualizing the full potential of NMR to explore GPCR conformational dynamics using receptors compatible with E. coli expression systems