Transient contacts for ligand recognition and modulation of receptor activation by Y1R and Y2R N termini (B03)

• Subject Area: Biochemistry ; General Genetics and Functional Genome Biology ; Bioinformatics and Theoretical Biology ; Biological and Biomimetic Chemistry ; Biophysics ; Endocrinology, Diabetology, Metabolism ; Pharmacology ; Structural Biology ; Cell Biology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421152132

The structures and functions of Y1R’s and Y2R’s N termini are still largely elusive despite recent cryo-electron microscopy studies on human Y1R and Y2R in complex with neuropeptide Y. Previous experiments from projects A03 and B03 (Sinz/Schmidt; Kaiser) strongly suggest an involvement of Y2R’s N-terminus during the ligand binding process and in the stabilization of defined signaling states of the receptor. We hypothesize that the N-terminus of Y2R might act as an intrinsically disordered region that forms transient interactions with ligands during the receptor recognition process, thereby affecting binding selectivity and specific receptor functions. We will use an integrative approach, combining state-of-the-art techniques in structural mass spectrometry and functional readouts, to correlate the dynamic contributions of Y1R’s and Y2R’s N termini with receptorspecific functions.

• DFG Programme: Collaborative Research Centres
• Subproject of: SFB 1423: Structural Dynamics of GPCR Activation and Signaling
• Applicant Institution: Universität Leipzig
• Project Heads: Dr. Anette Kaiser; Professorin Dr. Andrea Sinz