SFB 1423: Structural Dynamics of GPCR Activation and Signaling

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G protein-coupled receptors (GPCRs) are membrane receptors that play a central role in nearly all physiological functions of eukaryotic organisms. They bind a wide variety of agonists, and this binding causes conformational changes triggering activation of different intracellular proteins, such as G proteins and arrestins. GPCRs are highly attractive drug targets, and our current structural understanding makes a rational drug de-sign and development challenging, but increasingly feasible. However, the interplay between GPCRs, their ligands and intracellular signaling molecules is more complex than previously anticipated. GPCRs feature highly dynamic structures which exist in multiple different conformational states differing in their functional properties. These states are determined by spatially and temporally defined molecule-molecule interactions making GPCR signaling very complex. The CRC aims to elucidate structural hallmarks in various states of activation, which are linked to GPCR function. A broad spectrum of methods will be applied synergistically: computational techniques, structural methods, site-directed mutagenesis, crosslinking and mass spectrometry (MS), as well as functional cell-based analyses. The structural dynamics of peptide GPCRs and aGPCRs will be compared to those of the well-characterized receptors to identify common principles but also differences between receptor groups and classes. Novel aspects of signaling dynamics and protease-activated receptors will be included. Structural dynamics of GPCR activation and the modulation of receptor activation and signal selectivity, however, is the central question of all projects. Overall, we aim to answer the following questions: How can we turn snapshots obtained by structural analyses in the first funding period into a consistent picture of the dynamic processes of GPCR activation and signaling? How do different types of ligands affect the dynamics and trafficking of GPCRs, and the interaction with different effector proteins? How is the interplay of extracellular and intracellular signaling and coupling mechanism orchestrated? How can we use the knowledge of the structural dynamics to obtain signaling protein profiles and to predict ligands and their activity?