title: Mechanisms of inter- and intramolecular communication in GPCRs and G proteins.
abstract: This study represents the first attempt to couple, by computational experiments, the mechanisms of intramolecular and intermolecular communication concerning a guanidine nucleotide exchange factor (GEF), the thromboxane A2 receptor (TXA2R), and the cognate G protein (Gq) in its heterotrimeric GDP-bound state. Two-way pathways mediate the communication between the receptor-G protein interface and both the agonist binding site of the receptor and the nucleotide binding site of the G protein. The increase in solvent accessibility in the neighborhoods of the highly conserved E/DRY receptor motif, in response to agonist binding, is instrumental in favoring the penetration of the C-terminus of Gqalpha in between the cytosolic ends of H3, H5, and H6. The arginine of the E/DRY motif is predicted to be an important mediator of the intramolecular and intermolecular communication involving the TXA2R. The receptor-G protein interface is predicted to involve multiple regions from the receptor and the G protein alpha-subunit. However, receptor contacts with the C-terminus of the alpha5-helix seem to be the major players in the receptor-catalyzed motion of the alpha-helical domain with respect to the Ras-like domain and in the formation of a nucleotide exit route in between the alphaF-helix and beta6/alpha5 loop of Gqalpha. The inferences from this study are of wide interest, as they are expected to apply to the whole rhodopsin family, given also the considerable G protein promiscuity.
authors.affiliation: Dulbecco Telethon Institute (DTI), and Department of Chemistry, University of Modena and Reggio Emilia, via Campi 183, 41100 Modena, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Raimondi
authors.forename: Michele
authors.initials: M
authors.lastname: Seeber
authors.forename: Pier G De
authors.initials: PG
authors.lastname: Benedetti
authors.forename: Francesca
authors.initials: F
authors.lastname: Fanelli
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D019204:GTP-Binding Proteins / Q000737:chemistry*; D051379:Mice; D008956:Models, Chemical; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry*; D015398:Signal Transduction
chemical_list: D043562:Receptors, G-Protein-Coupled; D019204:GTP-Binding Proteins