To overcome these limitations the proposed CRC will elucidate the impact of the structural dynamics on GPCR function. A variety of methods ranging from ligand design and development, X-ray crystallography, cryogenic electron microscopy (cryo-EM) and magnetic resonance-based structural analyses (NMR and EPR), mutagenesis, functional analyses and fluorescence-based methods up to computer modeling and simulation techniques are combined synergistically. Peptide ligand receptors and adhesion GPCRs (aGPCR) represent the focus of the current proposal, as they are not only understudied but the flexible ligand and the large N-termini complicate the picture. The structural dynamics of peptide ligands and aGPCRs will be compared to well-characterized adrenergic or muscarinic receptors and rhodopsin to identify common principles but also differences between receptor groups and classes. Structural dynamics of ligand binding, activation and signal modulation, however, is the central question of all projects.
Thus, we aim to answer the following questions: How can we turn structural snapshots into a coherent picture of the dynamic processes of GPCR activation, signaling and trafficking? How can we develop a holistic concept of GPCRs that allows forecasting of activity? How can we improve our knowledge on structural dynamics to design ligands with predicted efficacy?