title: Structural Mechanisms of Voltage Sensing in G Protein-Coupled Receptors.
abstract: G-protein-coupled receptors (GPCRs) form the largest superfamily of membrane proteins and one-third of all drug targets in humans. A number of recent studies have reported evidence for substantial voltage regulation of GPCRs. However, the structural basis of GPCR voltage sensing has remained enigmatic. Here, we present atomistic simulations on the δ-opioid and M2 muscarinic receptors, which suggest a structural and mechanistic explanation for the observed voltage-induced functional effects. The simulations reveal that the position of an internal Na(+) ion, recently detected to bind to a highly conserved aqueous pocket in receptor crystal structures, strongly responds to voltage changes. The movements give rise to gating charges in excellent agreement with previous experimental recordings. Furthermore, free energy calculations show that these rearrangements of Na(+) can be induced by physiological membrane voltages. Due to its role in receptor function and signal bias, the repositioning of Na(+) has important general implications for signal transduction in GPCRs.
authors.affiliation: Computational Biology, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK; Physics, School of Science and Engineering, University of Dundee, Nethergate, Dundee DD1 4NH, UK.
authors.forename: Owen N
authors.initials: ON
authors.lastname: Vickery
authors.affiliation: Forschungszentrum Jülich GmbH, Institute of Complex Systems, Zelluläre Biophysik (ICS-4), Leo-Brandt-Strasse, 52428 Jülich, Germany.
authors.forename: Jan-Philipp
authors.initials: JP
authors.lastname: Machtens
authors.affiliation: Computational Biology, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK; Physics, School of Science and Engineering, University of Dundee, Nethergate, Dundee DD1 4NH, UK.
authors.forename: Giulia
authors.initials: G
authors.lastname: Tamburrino
authors.affiliation: Lead Identification and Optimization Support, Boehringer Ingelheim Pharma GmbH & Co KG, 88397 Biberach an der Riss, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Seeliger
authors.affiliation: Computational Biology, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK; Physics, School of Science and Engineering, University of Dundee, Nethergate, Dundee DD1 4NH, UK. Electronic address: u.zachariae@dundee.ac.uk.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Zachariae
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D006801:Humans; D015640:Ion Channel Gating; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D043585:Receptor, Muscarinic M2 / Q000737:chemistry / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000737:chemistry / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*
chemical_list: D043585:Receptor, Muscarinic M2; D043562:Receptors, G-Protein-Coupled; D017465:Receptors, Opioid, delta; D012964:Sodium