About our research 

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?

The SFB1423 is divided into four major groups:

  • Identification of structural snapshots of peptide and adhesion GPCRs
  • GPCR activity is modulated by distinct signals that lead to stabilization of active receptor conformations, which will be studied by
  • Different conformations will lead to different signaling, e.g. G protein/arrestin bias, Gi/Gs dual coupling, cis/trans-signaling
  • Peptide synthesis and membrane protein (GPCR) expression & Computational models of structure, dynamics and evolution of GPCRs 

Scheerer

Structural elucidation of neuropeptide GPCRs

Huster, Hildebrand

Investigation of the structure and dynamics of the ghrelin/GHS receptor complex

Schmidt, Sinz

Characterizing the molecular interactions of Y1 and Y2 receptors with NPY

Huster, Beck-Sickinger

Characterizing the molecular interaction between the Y receptor and arrestin

Scheerer, Sphan, Schönberg

Structures of adhesion GPCR by cryo-electron microscopy

Sträter, Langenhan

Enzymology of autoproteolysis and signaling function of the GAIN domain in adhesion GPCRs

Meiler

Innovative Rosetta algorithms for comparative modeling and docking of GPCRs

Beck-Sickinger

Molecular mechanisms of allosteric modulators at Y-receptors

Biebermann, Kühnen

Melanocortin 4 receptor signaling revisited: from ligand/receptor interphase to signaling modulation

Kaiser

Role of extracellular loop interactions in NPY receptor activation

Coin

Mapping binding sites of NPY peptides on the Y5 receptor using genetically encoded crosslinkers

Liebscher

Structural consequences of adhesion GPCR activation

Scholz, Langenhan

Dynamic modulation of adhesion GPCR function through complex formation

Stadler, Hildebrand

Evolution of functional selectivity in GPCR signal transduction

Annibale, Lohse

Microscopic methods to study how GPCR dynamics and localization impact signaling specificity

Prömel, Schöneberg

The neglected receptor N terminus – signal filter, signal integration, trans-signaling of adhesion GPCR

Bock, Coin

Structural dynamics of allosteric coupling in GPCRs

Beck-Sickinger, Schöneberg

Central Administration

Huster

Integrated Research Training Group (IRTG)

Scheerer, Beck-Sickinger

Peptide synthesis and membrane protein (GPCR) expression

Meiler, Stadler, Hildebrand

Computational models of structure, dynamics and evolution of GPCRs