title: Buried ionizable networks are an ancient hallmark of G protein-coupled receptor activation.
abstract: Seven-transmembrane receptors (7TMRs) have evolved in prokaryotes and eukaryotes over hundreds of millions of years. Comparative structural analysis suggests that these receptors may share a remote evolutionary origin, despite their lack of sequence similarity. Here we used structure-based computations to compare 221 7TMRs from all domains of life. Unexpectedly, we discovered that these receptors contain spatially conserved networks of buried ionizable groups. In microbial 7TMRs these networks are used to pump ions across the cell membrane in response to light. In animal 7TMRs, which include light- and ligand-activated G protein-coupled receptors (GPCRs), homologous networks were found to be characteristic of activated receptor conformations. These networks are likely relevant to receptor function because they connect the ligand-binding pocket of the receptor to the nucleotide-binding pocket of the G protein. We propose that agonist and G protein binding facilitate the formation of these electrostatic networks and promote important structural rearrangements such as the displacement of transmembrane helix-6. We anticipate that robust classification of activated GPCR structures will aid the identification of ligands that target activated GPCR structural states.
authors.affiliation: Departments of Biochemistry and Biophysics and disom@unc.edu hdohlman@med.unc.edu.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Isom
authors.affiliation: Departments of Biochemistry and Biophysics and Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 disom@unc.edu hdohlman@med.unc.edu.
authors.forename: Henrik G
authors.initials: HG
authors.lastname: Dohlman
mesh_terms: D000465:Algorithms; D001105:Archaea / Q000378:metabolism; D019843:Archaeal Proteins / Q000378:metabolism; D001419:Bacteria / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D001436:Bacteriorhodopsins / Q000737:chemistry; D019295:Computational Biology; D030562:Databases, Protein; D004837:Epinephrine / Q000737:chemistry; D019143:Evolution, Molecular; D006863:Hydrogen-Ion Concentration; D007477:Ions / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D018377:Neurotransmitter Agents / Q000737:chemistry; D009638:Norepinephrine / Q000737:chemistry; D055355:Opsins / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012243:Rhodopsin / Q000737:chemistry
chemical_list: D019843:Archaeal Proteins; D001426:Bacterial Proteins; D007477:Ions; D008024:Ligands; D018377:Neurotransmitter Agents; D055355:Opsins; D043562:Receptors, G-Protein-Coupled; D001436:Bacteriorhodopsins; D012243:Rhodopsin; D009638:Norepinephrine; D004837:Epinephrine
keywords: 7-transmembrane receptor; G protein-coupled receptor; buried charge; molecular evolution; structural bioinformatics