Detecting and directing molecular interactions that switch the functional state of G-protein coupled receptors

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G protein-coupled receptors (GPCRs) represent the largest class of membrane proteins (MPs) that are involved in virtually every physiological process. Understanding GPCR function at a molecular level poses one of the most important challenges to modern biology, medicine, and pharmacology. Despite the intense focus this family of proteins has received, an accurate mechanistic description of their action remains unsolved. Thus, it is of great importance to understand the inter- and intramolecular interactions that define the functional state of GPCRs. Single-molecule force spectroscopy (SMFS) of MPs is a recently established method that allows for the detection and characterization of the interactions that determine the functional state of MPs in their native environment. This project will therefore utilize this modern biophysical approach to gain insight into the function of GPCRs that have been previously unattainable using traditional methods. With this knowledge we will test and optimize ligand-like compounds to modulate function of GPCRs. Our approach will detail molecular interactions within the membrane embedded GPCR in the native state, how the pathological state of these receptors is attained, and how mutant GPCRs can be rescued by a ligand to display the native state.