Photo-Cross-Linkers Incorporated Into G-Protein-Coupled Receptors In Mammalian Cells: A Ligand Comparison

摘要

Although G-protein coupled receptors (GPCRs) are the molecular target of almost half of today's pharmaceuticals, little is known about the molecular basis of the specific interaction with their ligands, owing to the difficulty of obtaining spectroscopic data for such highly flexible and complex systems integrated in the cell membrane. A powerful experimental approach to investigate ligand-receptor interactions in a native environment is the use of photoaffinity cross-linking, which usually involves photo-activatable cross-linkers installed into chemically achievable ligands to establish spatial constraints in the ligand-receptor complex. However, only a few positions within the ligand can be modified with the photo-cross-linker without affecting binding or signaling behavior. This limitation prevents comprehensive mapping of the ligand-receptor interaction and prevents comparison of ligands with different pharmacological properties.