Structural elucidation of activity regulation at GPCRs involved in metabolism and immune responses (A01)

• Subject Area: Structural Biology ; Biophysics ; Endocrinology, Diabetology, Metabolism ; Pharmacology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421152132

The melanocortin-4 receptor (MC4R) is a highly potent pharmacological target for the treatment of obesity, as it contributes significantly to the regulation of body weight and a high number of receptor variants have been identified in obese or overweight patients. Project A01 aims to determine high-resolution 3D structures of MC4R in yet unknown conformations and complexes associated with specific functional properties and pathogenic conditions. The goal is to gain a more detailed understanding of the impact of internal and external factors on receptor signaling. The project will be focus on complexes between MC4R and various ligands with the G-protein subtype Gq/11, with arrestin and with the interacting transmembrane protein melanocortin-2 receptor accessory protein 2 (MRAP2). In addition, several MC4R variants with pathogenic functional alterations will be structurally studied. To achieve these objectives, advanced membrane protein production technologies, biophysical and cell-based assays, protein X-ray crystallography and cryo-electron microscopy are ap-plied. The gained insights are fundamental for the understanding of activation, selectivity, transient and allosteric processes at this receptor and for the development and optimization of pharmacological tools such as melanocortin derivatives and novel nonpeptidic drugs.

• DFG Programme: Collaborative Research Centres
• Subproject of: SFB 1423: Structural Dynamics of GPCR Activation and Signaling
• Applicant Institution: Universität Leipzig
• Project Head: Dr. Patrick Scheerer