DFG/Collaborative Research Center 1423:
Structural Dynamics of GPCR Activation and Signaling
Funding period: 2020 – 2021 – 2022 – 2023
Project identifier: German Research Foundation (DFG) – Project number 421152132
Research areas: Biochemistry, Structural Biology, Biophysics, Bioinformatics, Bioorganic Chemistry, Molecular Pharmacology
Coordinating university: Leipzig University, Augustusplatz 10, 04109 Leipzig
Research intrest: 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. The understanding of these molecular processes has been greatly advanced by crystal structures and a variety of direct and indirect in vitro analyses. GPCRs are highly attractive drug targets and our growing structural understanding puts a rational drug design and development within reach. However, the interplay between GPCRs and their ligands and intracellular signaling molecules is more complex than previously anticipated. GPCRs exist in multiple, highly dynamic structural states, which differ in their functional properties. These states are determined by spatially and temporally distinct molecule-molecule interactions complicating GPCR signaling, limiting our understanding of these processes, and our ability to rationally design drugs.
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?