SFB 1423:  Structural Dynamics of GPCR Activation and Signaling

• Subject Area: Biology ; Chemistry ; Medicine
• Term: since 2020
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421152132

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?

• DFG Programme: Collaborative Research Centres

Current projects

• A01 - Structural elucidation of activity regulation at GPCRs involved in metabolism and immune responses (Project Head Scheerer, Patrick )
• A02 - Investigation of the structure and dynamics of the ghrelin/GHS receptor complex (Project Heads Hildebrand, Peter ;  Huster, Ph.D., Daniel ;  Schoeder, Clara )
• A03 - The role of conformational dynamics for Y receptor activation (Project Heads Elgeti, Matthias ;  Schmidt, Peter ;  Sinz, Andrea )
• A04 - Characterizing the molecular interactions between Y receptors and arrestin (Project Heads Beck-Sickinger, Annette G. ;  Huster, Ph.D., Daniel )
• A05 - Structures of adhesion GPCR by cryo-electron microscopy (Project Heads Scheerer, Patrick ;  Schöneberg, Torsten ;  Spahn, Christian M. T. )
• A06 - Enzymology of autoproteolysis and signaling function of the GAIN domain in adhesion GPCRs (Project Heads Langenhan, Tobias ;  Sträter, Norbert )
• A07 - Innovative artificial intelligence algorithms for modeling and docking of GPCRs (Project Head Meiler, Jens )
• B01 - Molecular mechanisms of allosteric modulators at Y-receptors (Project Head Beck-Sickinger, Annette G. )
• B02 - Signaling dynamics of MC4R: development of advanced treatment strategies (Project Heads Biebermann, Heike ;  Kühnen, Peter )
• B03 - Transient contacts for ligand recognition and modulation of receptor activation by Y1R and Y2R N termini (Project Heads Kaiser, Anette ;  Sinz, Andrea )
• B04 - Exploring topology and dynamics of molecular interactions at Y receptors in living cells via non-canonical amino acids (Project Head Coin, Irene )
• B05 - Signal integration and specification of adhesion GPCRs (Project Head Liebscher, Ines )
• B06 - Dynamic modulation of adhesion GPCR function through complex formation (Project Heads Langenhan, Tobias ;  Scholz, Nicole )
• C01 - Specificity and dynamics in signaling of peptide activated GPCRs (Project Heads Hildebrand, Peter ;  Stadler, Peter Florian )
• C04 - The neglected receptor N terminus - signal filter, signal integration, trans-signaling of adhesion GPCR (Project Heads Prömel, Simone ;  Schöneberg, Torsten )
• C05 - Structural dynamics of allosteric coupling in GPCRs (Project Heads Bock, Andreas ;  Coin, Irene )
• C06 - Structure-, localization-, metabolism- and ligand-dependent signaling bias of metab-olite-sensing GPCRs (Project Head Stäubert, Claudia )
• C07 - Allosteric regulation of PAR1 biased signaling by tethered peptide ligands and receptor oligomerization (Project Heads Isermann, Berend ;  Künze, Georg )
• C08 - Mechanisms of receptor localization and localized signaling (Project Heads Bock, Andreas ;  Lohse, Martin J. )
• Z01 - Central Administration (Project Head Beck-Sickinger, Annette G. )
• Z02 - Integrated Research Training Group (MGK) (Project Head Huster, Ph.D., Daniel )
• Z03 - Peptide synthesis and membrane protein (GPCR) expression (Project Heads Beck-Sickinger, Annette G. ;  Scheerer, Patrick )
• Z04 - Data management and computational models of structure and dynamics, and evolution of GPCRs (Project Heads Hildebrand, Peter ;  Meiler, Jens ;  Stadler, Peter Florian )

Completed projects

• C03 - Microscopic methods to study how GPCR dynamics and localization impact signaling specificity (Project Heads Annibale, Paolo ;  Lohse, Martin J. )

• Applicant Institution: Universität Leipzig
• Participating University: Heinrich-Heine-Universität Düsseldorf; Martin-Luther-Universität Halle-Wittenberg
• Participating Institution: Charité - Universitätsmedizin Berlin
• Spokesperson: Professorin Dr. Annette G. Beck-Sickinger