G protein coupled receptors (GPCRs) are a class of membrane receptors that transmits extracellular signals into the cell. They can be activated by a diverse set of ligands including small molecules, hormones, neurotransmitters, or photons and are targeted by a third of currently marketed drugs. Endogenous ligands and drugs may exhibit different efficacy profiles, ranging from full activation to complete inactivation of a signalling pathway. The key to the selective interaction with signalling partners in response to ligand binding lies in the conformational flexibility of the membrane receptors. Previous research has extensively studied the three-dimensional structures of GPCRs and their signalling. However, the link between active conformations and signalling is still missing.
In this project, we are filling this gap by linking the three-dimensional structure of the receptor to signalling using a combination of biophysical experiments, computational analyses and high throughput signalling approaches. Our objectives are to further our understanding of the conformational changes in GPCRs and how they are linked to signalling. Which of the conformational changes observed are important for signalling and which ones are not? Which residues of the receptor are the most important ones for translating a ligand signal into an intracellular signal? Can this process be modified, either through changes in the ligand or through modulation of signal transduction at a later stage?
Better understanding the molecular basis behind signalling, including the conformational changes that the receptor undergoes upon activation, are important for the development of better drugs with fewer side effects. Understanding how exactly ligand binding is converted into an intracellular signalling event will help researchers modify existing ligands or help them design new ligands with better characteristics.
In conclusion, we have developed a framework for integrating pharmacological and structural data in this project. This allows us to determine which parts of the receptor are key for its functions, which parts are structurally important, pharmacologically important, or both. This improves our interpretation of both pharmacological and structural data. Our approach can be applied to other proteins where functional and structural data are available at similar resolution.
