The inner workings of the μ-opioid receptor: Elucidating the role of individual residues in translating ligand binding to G protein activation

• Applicant: Dr. Franziska Heydenreich
• Subject Area: Biochemistry ; Bioinformatics and Theoretical Biology ; Biophysics ; Pharmacology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 553775064

The gamma-opioid receptor (MOR) is a medically highly relevant G protein-coupled receptor (GPCR) and a major target of pain medications. However, current medications still entail side effects such as dependence and respiratory depression, they may even be fatal. Here, we propose to analyze the effect of 399 mutants of the MOR on intracellular signaling via one of its main signaling partners, the G protein Gi, in response to two compounds: the safe endogenous ligand met-enkephalin and the widely used painkiller but potentially deadly drug morphine. We will determine the role of each residue for receptor pharmacology, generate a functional map of the orthosteric binding site linking ligand atoms to intracellular effects and identify the structurally and functionally most relevant residues governing the activation of Gi by the receptor. We will show how the ligand- and G protein-binding sites are connected by allosteric networks and how these may be influenced by allosteric modulators to alter receptor signaling. Finally, we will analyze how functionally relevant amino acids and allosteric networks uncovered here compare to those determined for another GPCR, the Gs-coupled β2-adrenergic receptor. The overlap between these sets of residues will point us towards a potential unified activation mechanism while the differences will highlight receptor-specific activation fingerprints. With this work, we aim to provide an in-depth understanding of the molecular mechanisms of G protein activation and how these can be exploited to improve the design of drugs, especially safer analgesics with less pronounced side effects.

• DFG Programme: Research Grants