Diversity and pharmacology of oxytocin/vasopressin signaling

Cellular receptors, such as the family of G protein-coupled receptors (GPCRs), have a long-standing position as the largest drug target family. Still, for most drugs it is still unknown how they can selectively recognize a specific receptor and thus give rise to the desired therapeutic response (or harmful side-effects). Understanding how a ligand discriminates between closely related receptors would substantially enhance our knowledge of the physiological roles, which in turn facilitates the design of therapeutics with selective action at a given receptor. To advance our understanding of the molecular mechanisms of ligand/receptor recognition this project will focus on the oxytocin/vasopressin signaling system as model, since (i) it plays a key role in human health and disease, (ii) there exists vast information on structure-activity relationship of ligands/receptors, and (iii) and it is highly conserved through the animal kingdom to allow the discovery of novel ligand/receptor pairs. This project will lead to the discovery of unique, nature-derived peptide hormones to probe GPCR pharmacology. Understanding the molecular determinants that govern ligand binding and selectivity, will advance the rational design of better drug leads with less side effects and could lead to the development of clinically useful diagnostic tools or therapeutics of the important class of cellular drug target receptors, GPCRs.