PLoS ONE (Jan 2013)

Active-state models of ternary GPCR complexes: determinants of selective receptor-G-protein coupling.

  • Ralf C Kling,
  • Harald Lanig,
  • Timothy Clark,
  • Peter Gmeiner

DOI
https://doi.org/10.1371/journal.pone.0067244
Journal volume & issue
Vol. 8, no. 6
p. e67244

Abstract

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Based on the recently described crystal structure of the β2 adrenergic receptor--Gs-protein complex, we report the first molecular-dynamics simulations of ternary GPCR complexes designed to identify the selectivity determinants for receptor-G-protein binding. Long-term molecular dynamics simulations of agonist-bound β2AR-Gαs and D2R-Gαi complexes embedded in a hydrated bilayer environment and computational alanine-scanning mutagenesis identified distinct residues of the N-terminal region of intracellular loop 3 to be crucial for coupling selectivity. Within the G-protein, specific amino acids of the α5-helix, the C-terminus of the Gα-subunit and the regions around αN-β1 and α4-β6 were found to determine receptor recognition. Knowledge of these determinants of receptor-G-protein binding selectivity is essential for designing drugs that target specific receptor/G-protein combinations.