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

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...

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Autores principales:	Ralf C Kling, Harald Lanig, Timothy Clark, Peter Gmeiner
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/242c2f9276914c6d9e9b32fa55a9ca5a
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spelling	oai:doaj.org-article:242c2f9276914c6d9e9b32fa55a9ca5a2021-11-18T07:40:19ZActive-state models of ternary GPCR complexes: determinants of selective receptor-G-protein coupling.1932-620310.1371/journal.pone.0067244https://doaj.org/article/242c2f9276914c6d9e9b32fa55a9ca5a2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23826246/?tool=EBIhttps://doaj.org/toc/1932-6203Based 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.Ralf C KlingHarald LanigTimothy ClarkPeter GmeinerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 6, p e67244 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ralf C Kling Harald Lanig Timothy Clark Peter Gmeiner Active-state models of ternary GPCR complexes: determinants of selective receptor-G-protein coupling.
description	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.
format	article
author	Ralf C Kling Harald Lanig Timothy Clark Peter Gmeiner
author_facet	Ralf C Kling Harald Lanig Timothy Clark Peter Gmeiner
author_sort	Ralf C Kling
title	Active-state models of ternary GPCR complexes: determinants of selective receptor-G-protein coupling.
title_short	Active-state models of ternary GPCR complexes: determinants of selective receptor-G-protein coupling.
title_full	Active-state models of ternary GPCR complexes: determinants of selective receptor-G-protein coupling.
title_fullStr	Active-state models of ternary GPCR complexes: determinants of selective receptor-G-protein coupling.
title_full_unstemmed	Active-state models of ternary GPCR complexes: determinants of selective receptor-G-protein coupling.
title_sort	active-state models of ternary gpcr complexes: determinants of selective receptor-g-protein coupling.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/242c2f9276914c6d9e9b32fa55a9ca5a
work_keys_str_mv	AT ralfckling activestatemodelsofternarygpcrcomplexesdeterminantsofselectivereceptorgproteincoupling AT haraldlanig activestatemodelsofternarygpcrcomplexesdeterminantsofselectivereceptorgproteincoupling AT timothyclark activestatemodelsofternarygpcrcomplexesdeterminantsofselectivereceptorgproteincoupling AT petergmeiner activestatemodelsofternarygpcrcomplexesdeterminantsofselectivereceptorgproteincoupling
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Active-state models of ternary GPCR complexes: determinants of selective receptor-G-protein coupling.

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