The role of conformational dynamics for Y receptor activation (A03)

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

In order to limit adverse effects during treatment it is of primary pharmacological interest to develop therapeutics specifically binding to either Y1R or Y2R subtype, and bias downstream signaling (functional selectivity). Since YRs feature high conformational flexibility, we aim to elucidate the structural underpinnings of subtype specificity and functional selectivity using magnetic resonance spectroscopic methods suitable for resolving and characterizing conformational ensembles. For these experiments, we will stabilize the relevant receptor conformations using known subtype specific derivatives of endogenous peptide ligands. Accordingly, we will increase the population of conformations responsible for functional selectivity by binding of functionally biased ligands, transducer proteins or its mimetics. The results will be integrated with available high-resolution structures using computational methods, providing new leads for computeraided drug discovery.

• DFG Programme: Collaborative Research Centres
• Subproject of: SFB 1423: Structural Dynamics of GPCR Activation and Signaling
• Applicant Institution: Universität Leipzig
• Project Heads: Dr. Matthias Elgeti; Dr. Peter Schmidt; Professorin Dr. Andrea Sinz, until 12/2023