Allosteric regulation of PAR1 biased signaling by tethered peptide ligands and receptor oligomerization (C07*)

• Subject Area: Cell Biology ; Bioinformatics and Theoretical Biology ; Pharmacology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421152132

Our project will address the question how different tethered peptide agonists of protease-activated receptor 1 (PAR1) generated by thrombin or activated protein C (aPC) drive receptor signaling via different G protein or arrestin pathways. To achieve this, we will (i) determine the binding modes of thrombin- and aPC-generated tethered peptides, (ii) determine the signaling dynamics of PAR1 with G proteins and arrestins, (iii) elucidate molecular features on PAR1 and transducer proteins that impart coupling specificity and (iv) study the binding mode and molecular mode of action of parmodulins, small PAR1 biased ligands. We use experimental and simulation tools, including non-canonical amino acid-based crosslinking, mutagenesis coupled with different PAR1 functional readouts, molecular modeling and MD simulation.

• DFG Programme: Collaborative Research Centres
• Subproject of: SFB 1423: Structural Dynamics of GPCR Activation and Signaling
• Applicant Institution: Universität Leipzig
• Project Heads: Professor Dr. Berend Isermann; Dr. Georg Künze