Covalent agonists for studying G protein-coupled receptor activation

We recently published “Covalent agonists for studying G protein-coupled receptor activation” in Proceedings of the National Academy of Sciences.

Protein crystallography has greatly contributed to our understanding of the structure and function of G protein-coupled receptors (GPCRs). Recent success in the structural investigation of active GPCR conformations was guided by the application of high-affinity agonists and G proteins or G protein mimetic nanobodies. However, poor affinities of agonists prevent the formation of diffraction-quality crystals and hamper the generation of state-specific nanobodies. To overcome this limitation, we present a general approach to covalently binding molecular tools for the construction of stable ligand-receptor complexes capable of G protein activation. Besides the promotion of structural studies, tethered agonist-GPCR complexes may find application in biochemical and biophysical experiments that require reliable labeling of distinct receptor populations, underlining the versatility of covalent agonists for studying GPCR activation.