A structure – activity relationship study on position –2 of the Gas C-terminal peptide able to inhibit Gs activation by A2A adenosine receptor

For some years synthetic peptides corresponding to the C-terminal sequence of Ga proteins represented an useful tool to study the molecular mechanism of the interaction between these proteins and the G protein coupled receptors. Recently, we have focused our attention on the study of the A2A receptor/Gs protein system. We have synthesised a series of 11-mer peptides from the Gas Cterminus in which residue at position-2 (Leu393) has been alternatively substituted with amino acids having different physicochemical properties. The aim of our work was to probe the role played by Leu393 in the receptor/Gas interaction. All synthetic peptides were tested for their ability to affect the adenylyl cyclase activity stimulated by agonist activation of A2A adenosine receptors. Our data point out a relevant role played by the side chain of this residue for a correct G protein/receptor coupling, even though the presence of other residues at position-2 of Gas C-terminus is tolerated. Furthermore, molecular dynamics calculations on the peptides having greater activity show a correlation between the spatial arrangement of the side chain of residue at position-2 and biological activity of synthetic peptides.