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PMID: 23826246 Published · epublish English Journal Article

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

PloS one ·Vol. 8 ·No. 6 ·2013-00-00 ·Pages e67244

Kling RC, Lanig H, Clark T, Gmeiner P

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.

MeSH Terms
Alanine/genetics Amino Acid Sequence Binding Sites Dopamine/metabolism GTP-Binding Protein alpha Subunits, Gi-Go/chemistry,metabolism GTP-Binding Proteins/metabolism Histidine/metabolism Ligands Models, Biological Molecular Dynamics Simulation Molecular Sequence Data Multiprotein Complexes/metabolism Mutagenesis Protein Structure, Secondary Receptors, Adrenergic, beta-2/chemistry,metabolism Receptors, Dopamine/chemistry,metabolism Receptors, G-Protein-Coupled/chemistry,metabolism Sequence Alignment Structural Homology, Protein
Chemicals
Ligands Multiprotein Complexes Receptors, Adrenergic, beta-2 Receptors, Dopamine Receptors, G-Protein-Coupled Histidine GTP-Binding Proteins GTP-Binding Protein alpha Subunits, Gi-Go Alanine Dopamine
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Kling Ralf C
Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Erlangen, Germany.
Lanig Harald
Clark Timothy
Gmeiner Peter
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Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0067244
Published
2013-00-00
Epub
2013-00-24
Pages
e67244
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC3691126
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pone.0067244 PMC Full Text View journal details
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