Structural dynamics of allosteric coupling in GPCRs (C05)

• Subject Area: Pharmacology ; Biochemistry
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421152132

The overall goal of this proposal is to understand the structural dynamics of allosteric coupling in GPCRs as the basis for ligand efficacy and its implications for receptor/transducer-coupling selectivity. In the first funding period, we have developed novel single-color GPCR activation biosensors (so-called STICCERs) that report in real-time on the agonist-related conformational dynamics of extracellular receptor domains in intact cells. Using STICCER technology, we have uncovered that GPCR activation occurs by sequential conformational changes that eventually, after having passed several intermediate states, result in ligand-specific receptor states. In the upcoming funding period, we will develop dual-color allosteric GPCR biosensors that allow following activation-related extra- and intracellular conformational changes simultaneously. This technology will determine the kinetics of the entire allosteric coupling process at various GPCRs, with a major focus on peptide receptors. Finally, we will investigate whether the distinct, ligand-specific GPCR activation states translate into ligand-specific profiles of transducer coupling.

• DFG Programme: Collaborative Research Centres
• Subproject of: SFB 1423: Structural Dynamics of GPCR Activation and Signaling
• Applicant Institution: Universität Leipzig
• Project Heads: Professor Dr. Andreas Bock; Professorin Dr. Irene Coin