Active-State Models of Ternary GPCR Complexes: Determinants of Selective Receptor-G-Protein Coupling

Language
en
Document Type
Article
Issue Date
2013-07-09
Issue Year
2013
Authors
Kling, Ralf C.
Lanig, Harald
Clark, Timothy
Gmeiner, Peter
Editor
Abstract

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.

Journal Title
PLoS ONE 8.6 (2013): 01.07.2013 <http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0067244>
Citation
PLoS ONE 8.6 (2013): 01.07.2013 <http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0067244>
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