Deciphering the different activation modes for a few aGPCRs has only just opened the tool box of receptor modulation and potential pharmacological intervention. A few ligands have been assigned to their respective target domains within the receptor sequence; the prerequisites as well as consequences on a structural or functional level are scarcely known. The formation of extracellular dimers or even polymers between receptor and interaction partners has been shown and it has been suggested that aGPCRs are part of intracellular networks. It is currently unknown how the exposure of the tethered agonist sequence can take place.
Members of WG2 are exploring the integration of aGPCRs into the cellular context and are working on gaining a more in-depth understanding on how this protein network could potentially lead to the establishment of an active receptor conformation.
To achieve these goals, WG2 focuses on gaining structural information from crystals, cryo-EM, nuclear magnetic resonance (NMR) and Double electron–electron resonance (DEER) spectroscopy. Further, downstream signaling analyses and predictive modelling will be established. From these studies, structure-function information will be extracted to provide information on aGPCR domain or whole receptor structures. Further, models of aGPCR function based on their signals and structure-function analyses will be obtained.