signalling dynamics SIGNED

Project "signalling dynamics" data sheet

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 Project objective

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 the proposed project, first I will use exhaustive single-point mutagenesis coupled to functional assays to determine how the sequence and secondary structure of GPCRs contribute to signaling. Second, biophysical techniques studying protein conformations will help us to understand the connection between conformations and signalling outcome. These techniques give insights into the conformational fingerprints of the receptor. The link to signalling will be achieved by biasing the receptor towards a selected signalling partner either though addition of the selected signalling partner or the insertion of specific mutations tested in the first part of the project. Finally, I will use computational techniques to compare the activation of signalling partners in different GPCRs. With my research I hope to improve our understanding of the molecular basis of membrane protein function and contribute to the development of strategies for the design of more specific drugs with fewer side effects.