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

ABSTRACT: Based on the recently described crystal structure of the ?2 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 ?2AR-G?s and D2R-G?i 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 ?5-helix, the C-terminus of the G?-subunit and the regions around ?N-?1 and ?4-?6 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.

SUBMITTER: Kling RC

PROVIDER: S-EPMC3691126 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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

Kling Ralf C RC Lanig Harald H Clark Timothy T Gmeiner Peter P

PloS one 20130624 6

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 intr ...[more]

PMID: 23826246

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