Harnessing G Protein-coupled Receptor Protein Dynamics for Precision Pharmacology
The ability of discovered molecules, often completely new to nature, to profoundly change human physiology is one of the crowning achievements of modern medicine. A common feature of one-third of current drugs is their shared family of targets, one of the over 700 G protein-coupled receptors (GPCRs) encoded in the human genome. Considerable progress over the past decade has revealed how drugs bind to their GPCR targets and induce their activity. These studies have exposed a significant complexity in the structures and dynamic movements of the GPCR proteins themselves. Harnessing this protein complexity with novel drugs promises a new era of therapeutics with tailored human physiology, often efficacious molecules devoid of side effects. A framework for rationally achieving this goal remains elusive.
This proposal aims to provide such a framework, with a focus on new approaches to address the opioid addiction epidemic. Molecules targeting the opioid receptors, like morphine, are the most effective drugs ever discovered for pain. Their lethal side effects, combined with their addictiveness, have yielded one of the greatest scourges within the pharmacopeia. Intriguingly, molecules that enable opioid receptors to signal selectively through one intracellular pathway among many, so called “biased agonists”, show promise as safer analgesics. We aim to understand such extraordinary ligand-specific signaling selectivity. First, we will determine the biochemical and structural basis of opioid receptor regulation by kinases and arrestins. Biased opioid agonists fail to induce interaction of receptors with these regulatory proteins and our studies to explain this will provide unprecedented insight into biased agonism for the broader GPCR family. Second, we will directly examine the structural ensembles of opioid receptors by developing new tools in protein biophysics. These studies will enable us to directly characterize the unique molecular interactions that biased opioid agonists make with their receptors, and how this leads to unique receptor conformations that fail to induce deleterious signaling events.
Analogous to the century-old discovery that targeting specific receptors among many would lead to “magic bullets”, we envision that targeting specific conformations among many of the same receptor will profoundly shape drug discovery. By merging protein biophysics with molecular pharmacology, we aim to provide a new foundation enabling such discovery.