Francesco Raimondi, Michele Seeber, Pier G. De Benedetti, and Francesca Fanelli
Dulbecco Telethon Institute (DTI), and Department of Chemistry, UniVersity of Modena and Reggio Emilia, Via Campi 183, 41100 Modena, Italy

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 GqR 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 R-subunit. However, receptor contacts with the C-terminus of the α5-helix seem to be the major players in the receptor- catalyzed motion of the R-helical domain with respect to the Ras-like domain and in the formation of a nucleotide exit route in between the αF-helix and β6/R5 loop of Gqα. 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.    

J. AM. CHEM. SOC. 2008, 130, 4310-4325   PMID: 18335928


Mechanisms of Inter- and Intramolecular Communication in GPCRs and G Proteins