Most of the available GPCR structures represent energetically stable inactive-state conformations. How and at which rates receptors shift between inactive and active states is still unclear. WG1 will fill in the gaps between the static X-ray snapshots using techniques that explicitly take into account dynamics, such as NMR, Fourier-transform infrared spectroscopy (FTIR), MD simulations and Förster Resonance Energy Transfer (FRET).
WG2: Biased Signaling
Intriguingly, different ligands that bind to the same GPCR protein are able to induce different downstream signalling protein pathways, resulting in pathway bias. This offers new venues for drug discovery and will minimise the risk of adverse side effects. Members of WG2 will develop and apply bias screening methodologies and assays to identify and further develop novel biased GPCR modulators. Biophysical approaches and molecular modelling studies using the novel ligands as functional probes will provide crucial insight into the structural determinants (receptor regions, conformations) of GPCRs that dictate biased signalling, which will tie in with the goals of WG1.
WG3: GPCR Lipid/Protein Interactions
Researchers in WG3 will investigate the interactions between GPCRs and partners that are not small molecules. This includes interactions with the various components of receptor-embedding membranes, which are known to influence GPCR function as well as receptor oligomerisation. WG3 will also study GPCR-protein interactions with, for example, other GPCR monomers, G proteins, and PDZ domains. Another focus will be posttranslational lipid modifications of GPCRs and G proteins that affect membrane binding, trafficking and signalling. WG3 members will use and further develop a wide range of techniques specific for protein-protein and protein-lipid interactions.
WG4: Discovery & Design of GPCR Ligands
WG4 will focus on the discovery, design and optimisation of small molecules that interact with GPCRs. This will provide new tracks in biomedical research and aid the other researchers in the Action in carrying out their tasks. Members of WG4 will seek and identify novel GPCR ligands for applications in medicinal chemistry (e.g. identification of new chemical series for GPCRs of high therapeutic interest; prediction of selectivity of GPCR ligands), chemical biology (e.g. chemical probes for investigating function and signalling of GPCRs; cf. WG2 and WG3), and structural biology (e.g. design of ligands to stabilise a particular GPCR conformation; cf. WG1).