title: Vibrational resonance, allostery, and activation in rhodopsin-like G protein-coupled receptors.
abstract: G protein-coupled receptors are a large family of membrane proteins activated by a variety of structurally diverse ligands making them highly adaptable signaling molecules. Despite recent advances in the structural biology of this protein family, the mechanism by which ligands induce allosteric changes in protein structure and dynamics for its signaling function remains a mystery. Here, we propose the use of terahertz spectroscopy combined with molecular dynamics simulation and protein evolutionary network modeling to address the mechanism of activation by directly probing the concerted fluctuations of retinal ligand and transmembrane helices in rhodopsin. This approach allows us to examine the role of conformational heterogeneity in the selection and stabilization of specific signaling pathways in the photo-activation of the receptor. We demonstrate that ligand-induced shifts in the conformational equilibrium prompt vibrational resonances in the protein structure that link the dynamics of conserved interactions with fluctuations of the active-state ligand. The connection of vibrational modes creates an allosteric association of coupled fluctuations that forms a coherent signaling pathway from the receptor ligand-binding pocket to the G-protein activation region. Our evolutionary analysis of rhodopsin-like GPCRs suggest that specific allosteric sites play a pivotal role in activating structural fluctuations that allosterically modulate functional signals.
authors.affiliation: Physics Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
authors.forename: Kristina N
authors.initials: KN
authors.lastname: Woods
authors.affiliation: Institute for Software Research, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Pfeffer
authors.affiliation: Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
authors.forename: Arpana
authors.initials: A
authors.lastname: Dutta
authors.affiliation: Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.|Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Judith
authors.initials: J
authors.lastname: Klein-Seetharaman
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D060066:Protein Interaction Maps; D017433:Protein Structure, Secondary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012243:Rhodopsin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D055068:Terahertz Spectroscopy / Q000379:methods; D014732:Vibration
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D012243:Rhodopsin