Jinpeng Sun, PhD, Professor and Chair, Biochemistry and Molecular Biology, Shandong University School of Medicine; Joint Professor, Peking University
G protein-coupled receptors are important transmembrane proteins which account for more than 30% of direct clinical drug targets. Two main signaling pathways, either mediated by different G protein subtype or arrestins, underlie most of 800 GPCR functions in human genome. Selective ligands targeting to one of the G protein- or arrestin-signaling through specific receptor, which is also called biased ligands, may have beneficial effects and delete the unwanted side effects compared with traditional full agonists or antagonists.
Recent structural studies unveiled that both receptor seven transmembrane core and phospho-C-tail engaged with arrestin interactions. Using unnatural amino acid incorporation and genetic expanding technologies, combined with biochemical and crystallographic approaches, we have provided direct experimental evidences that the receptor phosphorylation barcodes in their C-tails could be read by the phospho-pattern readers located in the arrestin, which is the combination of the phosphoate or negative-charged amino acids binding sites. Binding of each site allosterically produced unique arrestin conformations and correlated to selective arrestin downstream functions. Our results indicated that operation of receptor phospho-barcode could be an important strategy to modulate selective receptor functions, serving as an important aspect for developing biased receptor agonists as new therapies.