Mechanisms of inter- and intramolecular communication in GPCRs and G proteins

J Am Chem Soc. 2008 Apr 2;130(13):4310-25. doi: 10.1021/ja077268b. Epub 2008 Mar 12.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Computer Simulation
  • GTP-Binding Proteins / chemistry*
  • Mice
  • Models, Chemical
  • Molecular Sequence Data
  • Protein Conformation
  • Protein Structure, Tertiary
  • Receptors, G-Protein-Coupled / chemistry*
  • Signal Transduction


  • Receptors, G-Protein-Coupled
  • GTP-Binding Proteins