A structure-activity relationship study on position-2 of the Galpha(s) C-terminal peptide able to inhibit G(s) activation by A2A adenosine receptor.
For some years synthetic peptides corresponding to the C-terminal sequence of Galpha 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 A(2A) receptor-G(s) protein system. We have synthesised a series of 11-mer peptides from the Galpha(s) C-terminus in which residue at position-2 (Leu(393)) has been alternatively substituted with amino acids having different physico-chemical properties. The aim of our work was to probe the role played by Leu(393) in the receptor/Galpha(s) interaction. All synthetic peptides were tested for their ability to affect the adenylyl cyclase activity stimulated by agonist activation of A(2A) 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 Galpha(s) 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.
Grieco
Paolo
P
Dipartimento di Chimica Farmaceutica e Tossicologica, Università degli Studi di Napoli Federico II, Napoli, Italy.
Albrizio
Stefania
S
D'Ursi
Anna Maria
AM
Giusti
Laura
L
Mazzoni
Maria R
MR
Novellino
Ettore
E
Rovero
Paolo
P
D000262:Adenylyl Cyclases / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000737:chemistry*; D007930:Leucine / Q000737:chemistry; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation / Q000187:drug effects; D043683:Receptors, Adenosine A2 / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction; D013329:Structure-Activity Relationship
D010455:Peptides; D043683:Receptors, Adenosine A2; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases; D007930:Leucine