| Abstract
| - This study represents the first attempt to couple, by computational experiments, the mechanismsof 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 interfaceand both the agonist binding site of the receptor and the nucleotide binding site of the G protein. Theincrease in solvent accessibility in the neighborhoods of the highly conserved E/DRY receptor motif, inresponse to agonist binding, is instrumental in favoring the penetration of the C-terminus of Gqα in betweenthe cytosolic ends of H3, H5, and H6. The arginine of the E/DRY motif is predicted to be an importantmediator of the intramolecular and intermolecular communication involving the TXA2R. The receptor−Gprotein interface is predicted to involve multiple regions from the receptor and the G protein α-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 α-helical domain with respect to the Ras-like domain and in the formation of anucleotide exit route in between the αF-helix and β6/α5 loop of Gqα. The inferences from this study are ofwide interest, as they are expected to apply to the whole rhodopsin family, given also the considerable Gprotein promiscuity.
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