Molecular mechanisms of allosteric modulators at Y-receptors (B01)

• Subject Area: Biochemistry ; Biological and Biomimetic Chemistry
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421152132

This projects aims to identify the binding and activation mode of the peptide ligands pancreatic polypeptide (PP) and neuropeptide Y to the human Y receptors in the presence and absence of small molecule modula-tors. In the first funding period, we identified positive and negative allosteric modulators (PAMs,NAMs) at the Y4R, and identified relevant residues for the cryo-EM structure of Y1R, Y2R and Y4R. The fundamental structural insights from the cryo-EM will allow us now to characterize the different conformational states of YR in the presence of PAMs and NAMs and to develop rational concepts to understand and specifically design potent and selective allosteric modulators for other YR by using chimeric receptors, mutagenesis, binding, signalling and trafficking assays.

• DFG Programme: Collaborative Research Centres
• Subproject of: SFB 1423: Structural Dynamics of GPCR Activation and Signaling
• Applicant Institution: Universität Leipzig
• Project Head: Professorin Dr. Annette G. Beck-Sickinger