Signaling within Allosteric Machines: Signal Transmission Pathways Inside G Protein-Coupled Receptors

In recent years, our understanding of function of G protein-coupled receptors (GPCRs) has changed from a picture of simple signal relays, transmitting only a particular signal to a particular G protein heterotrimer, to versatile machines, capable of various responses to different stimuli and being modulated by various factors. Some recent reports provide not only the data on ligands/modulators and resultant signals induced by them, but also deeper insights into exact pathways of signal migration and mechanisms of signal transmission through receptor structure. Combination of these computational and experimental data sheds more light on underlying mechanisms of signal transmission and signaling bias in GPCRs. In this review we focus on available clues on allosteric pathways responsible for complex signal processing within GPCRs structures, with particular emphasis on linking compatible in silico- and in vitro-derived data on the most probable allosteric connections.

• Publication year

  2017

• Venue

  Molecules

• Publication date

  2017-07-01

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.3390/molecules22071188PMID 28714871PMCID 6152049
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Advances in Intelligent Systems and Computing - Selected Papers from the International Conference on Computer Science and Information Technologies, CSIT 2016, September 6-10 Lviv, Ukraine

  2017cited by this paper
• Residues W320 and Y328 within the binding site of the &mgr;‐opioid receptor influence opiate ligand bias

  2017cited by this paper
• Core engagement with β-arrestin is dispensable for agonist-induced vasopressin receptor endocytosis and ERK activation

  2017cited by this paper
• Activation mechanism of the G protein-coupled sweet receptor heterodimer with sweeteners and allosteric agonists

  2017influential reference
• Propagation of the Allosteric Modulation Induced by Sodium in the δ-Opioid Receptor.

  2017influential reference
• Crystal structure of the adenosine A2A receptor bound to an antagonist reveals a potential allosteric pocket

  2017cited by this paper
• Quaternary structure of a G-protein-coupled receptor heterotetramer in complex with Gi and Gs

  2016cited by this paper
• Dynamic Regulation of Quaternary Organization of the M1 Muscarinic Receptor by Subtype-selective Antagonist Drugs*

  2016cited by this paper
• G Protein-Coupled Receptor Heteromers.

  2016cited by this paper
• The dopamine D2 receptor dimer and its interaction with homobivalent antagonists: homology modeling, docking and molecular dynamics

  2016cited by this paper
• Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region

  2016cited by this paper
• Structure of CC Chemokine Receptor 2 with Orthosteric and Allosteric Antagonists

  2016influential reference
• Ultraslow Water-Mediated Transmembrane Interactions Regulate the Activation of A2A Adenosine Receptor.

  2016cited by this paper
• Basic Pharmacological and Structural Evidence for Class A G-Protein-Coupled Receptor Heteromerization

  2016cited by this paper
• Dynamic Cholesterol-Conditioned Dimerization of the G Protein Coupled Chemokine Receptor Type 4

  2016cited by this paper
• Cholesterol-dependent Conformational Plasticity in GPCR Dimers

  2016cited by this paper
• Molecular dynamics simulations and structure-based network analysis reveal structural and functional aspects of G-protein coupled receptor dimer interactions

  2016cited by this paper
• Structure-based discovery of opioid analgesics with reduced side effects

  2016cited by this paper
• Intracellular allosteric antagonism of the CCR9 receptor

  2016cited by this paper
• Receptor Activity-Modifying Proteins (RAMPs): New Insights and Roles.

  2016cited by this paper
• Computational methods for studying G protein-coupled receptors (GPCRs).

  2016influential reference
• How Oliceridine (TRV-130) Binds and Stabilizes a μ-Opioid Receptor Conformational State That Selectively Triggers G Protein Signaling Pathways.

  2016cited by this paper
• Conserved Mechanism of Conformational Stability and Dynamics in G-Protein-Coupled Receptors.

  2016cited by this paper
• Proposed Mode of Binding and Action of Positive Allosteric Modulators at Opioid Receptors

  2016cited by this paper
• Interplay between Two Allosteric Sites and Their Influence on Agonist Binding in Human μ Opioid Receptor

  2016cited by this paper
• Investigation of allosteric coupling in human β2-adrenergic receptor in the presence of intracellular loop 3

  2016cited by this paper
• Revealing Atomic-Level Mechanisms of Protein Allostery with Molecular Dynamics Simulations

  2016cited by this paper
• Mechanism of Assembly and Cooperativity of Homomeric and Heteromeric Metabotropic Glutamate Receptors.

  2016cited by this paper
• Bias Analyses of Preclinical and Clinical D2 Dopamine Ligands: Studies with Immediate and Complex Signaling Pathways

  2015influential reference
• Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu5 Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile).

  2015cited by this paper
• Generic GPCR residue numbers - aligning topology maps while minding the gaps.

  2015cited by this paper
• Propagation of conformational changes during μ-opioid receptor activation

  2015cited by this paper
• Major ligand-induced rearrangement of the heptahelical domain interface in a GPCR dimer.

  2015cited by this paper
• Thematic Minireview Series: New Directions in G Protein-coupled Receptor Pharmacology*

  2015cited by this paper
• Dual agonist occupancy of AT1-R-α2C-AR heterodimers results in atypical Gs-PKA signaling.

  2015cited by this paper
• Regulation of GPCR Anterograde Trafficking by Molecular Chaperones and Motifs.

  2015cited by this paper
• PDZ Protein Regulation of G Protein–Coupled Receptor Trafficking and Signaling Pathways

  2015cited by this paper
• Activation and Allosteric Modulation of Human μ Opioid Receptor in Molecular Dynamics

  2015influential reference
• Targeting β-arrestin2 in the treatment of l-DOPA–induced dyskinesia in Parkinson’s disease

  2015cited by this paper
• Functional water molecules in rhodopsin activation.

  2014cited by this paper
• Retinal ligand mobility explains internal hydration and reconciles active rhodopsin structures.

  2014cited by this paper
• The 2.1 Å Resolution Structure of Cyanopindolol-Bound β1-Adrenoceptor Identifies an Intramembrane Na+ Ion that Stabilises the Ligand-Free Receptor

  2014cited by this paper
• Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway

  2014cited by this paper
• G Protein–Coupled Receptor Oligomerization Revisited: Functional and Pharmacological Perspectives

  2014influential reference
• Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain

  2014cited by this paper
• Differences in allosteric communication pipelines in the inactive and active states of a GPCR.

  2014influential reference
• Single Molecule Analysis of Functionally Asymmetric G Protein-coupled Receptor (GPCR) Oligomers Reveals Diverse Spatial and Structural Assemblies*♦

  2014cited by this paper
• Recent computational advances in the identification of allosteric sites in proteins.

  2014cited by this paper
• Tyrosine 308 Is Necessary for Ligand-directed Gs Protein-biased Signaling of β2-Adrenoceptor*

  2014cited by this paper
• Communication over the Network of Binary Switches Regulates the Activation of A2A Adenosine Receptor

  2014cited by this paper
• Application of BRET for studying G protein-coupled receptors.

  2014cited by this paper
• Allosteric sodium in class A GPCR signaling.

  2014cited by this paper
• Protein Hotspot Prediction Using S-Transform

  2014cited by this paper
• Molecular control of δ-opioid receptor signalling

  2014cited by this paper
• Disruption of the Na+ ion binding site as a mechanism for positive allosteric modulation of the mu-opioid receptor

  2014cited by this paper
• μ-δ opioid receptor heteromer-specific signaling in the striatum and hippocampus.

  2014cited by this paper
• Cholesterol modulates the dimer interface of the β₂-adrenergic receptor via cholesterol occupancy sites.

  2014cited by this paper
• Structure of a Class C GPCR Metabotropic Glutamate Receptor 1 Bound to an Allosteric Modulator

  2014cited by this paper
• Transactivation of the PAR1-PAR2 Heterodimer by Thrombin Elicits β-Arrestin-mediated Endosomal Signaling*

  2013cited by this paper
• The role of water and sodium ions in the activation of the μ-opioid receptor.

  2013cited by this paper
• Computational identification of a transiently open L1/S3 pocket for reactivation of mutant p53

  2013cited by this paper
• Activation and allosteric modulation of a muscarinic acetylcholine receptor

  2013cited by this paper
• Structure-based molecular modeling approaches to GPCR oligomerization.

  2013cited by this paper
• Simulating G protein-coupled receptors in native-like membranes: from monomers to oligomers.

  2013cited by this paper
• Druggability Assessment of Allosteric Proteins by Dynamics Simulations in the Presence of Probe Molecules.

  2013cited by this paper
• ASD v2.0: updated content and novel features focusing on allosteric regulation

  2013cited by this paper
• Activation and dynamic network of the M2 muscarinic receptor

  2013cited by this paper
• Structure of the CCR5 Chemokine Receptor–HIV Entry Inhibitor Maraviroc Complex

  2013cited by this paper
• Mapping the intramolecular signal transduction of G‐protein coupled receptors

  2013cited by this paper
• Apo-ghrelin receptor forms heteromers with DRD2 in hypothalamic neurons and is essential for anorexigenic effects of DRD2 agonism.

  2012cited by this paper
• Circadian-Related Heteromerization of Adrenergic and Dopamine D4 Receptors Modulates Melatonin Synthesis and Release in the Pineal Gland

  2012cited by this paper
• Receptor Heteromerization Expands the Repertoire of Cannabinoid Signaling in Rodent Neurons

  2012cited by this paper
• The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling

  2012cited by this paper
• Distinct roles of metabotropic glutamate receptor dimerization in agonist activation and G-protein coupling

  2012cited by this paper
• Regulation of GPCR activity, trafficking and localization by GPCR‐interacting proteins

  2012influential reference
• High-resolution crystal structure of human Protease-Activated Receptor 1 bound to the antagonist vorapaxar

  2012cited by this paper
• Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor

  2012cited by this paper
• Sequential Inter- and Intrasubunit Rearrangements During Activation of Dimeric Metabotropic Glutamate Receptor 1

  2012cited by this paper
• Structural Basis for Allosteric Regulation of GPCRs by Sodium Ions

  2012cited by this paper
• Using Ligand-Mapping Simulations to Design a Ligand Selectively Targeting a Cryptic Surface Pocket of Polo-Like Kinase 1

  2012cited by this paper
• Sequential Conformational Rearrangements Dictate the Dynamics of Class C GPCR Activation

  2012cited by this paper
• Stimulus Bias Provides Evidence for Conformational Constraints in the Structure of a G Protein-coupled Receptor*

  2012cited by this paper
• Action of Molecular Switches in GPCRs - Theoretical and Experimental Studies

  2012cited by this paper
• Functional crosstalk and heteromerization of serotonin 5-HT2A and dopamine D2 receptors.

  2011cited by this paper
• Dimerization and ligand binding affect the structure network of A(2A) adenosine receptor.

  2011cited by this paper
• Discovery of β-Arrestin–Biased Dopamine D2 Ligands for Probing Signal Transduction Pathways Essential for Antipsychotic Efficacy

  2011cited by this paper
• Oligomerization of G protein-coupled receptors: biochemical and biophysical methods.

  2011cited by this paper
• Trends in the exploitation of novel drug targets

  2011cited by this paper
• Past, present and future of A(2A) adenosine receptor antagonists in the therapy of Parkinson's disease.

  2011cited by this paper
• Crystal Structure of the β2Adrenergic Receptor-Gs protein complex

  2011cited by this paper
• Oligomerization of G protein-coupled receptors: computational methods.

  2011cited by this paper
• Agonists at the δ‐opioid receptor modify the binding of µ‐receptor agonists to the µ–δ receptor hetero‐oligomer

  2010cited by this paper
• GPCR interacting proteins (GIPs) in the nervous system: Roles in physiology and pathologies.

  2010cited by this paper
• Monomeric rhodopsin is the minimal functional unit required for arrestin binding.

  2010cited by this paper
• Mapping the Druggable Allosteric Space of G-Protein Coupled Receptors: a Fragment-Based Molecular Dynamics Approach

  2010cited by this paper
• Monomeric Rhodopsin Is Sufficient for Normal Rhodopsin Kinase (GRK1) Phosphorylation and Arrestin-1 Binding*

  2010cited by this paper
• The endocannabinoid 2-arachidonylglycerol is a negative allosteric modulator of the human A3 adenosine receptor.

  2010cited by this paper
• Ligand binding and micro-switches in 7TM receptor structures.

  2009cited by this paper
• Hetero-oligomerization of CCR2, CCR5, and CXCR4 and the Protean Effects of “Selective” Antagonists*

  2009cited by this paper
• Quantifying Correlations Between Allosteric Sites in Thermodynamic Ensembles.

  2009cited by this paper

• Unlocking Multiscale Allosteric Mechanisms: Advanced Computational Strategies for Drug Discovery.

  2026cites this paper
• Allosteric modulation of gonadotropin receptors

  2023cites this paper
• Recent Studies on Serotonin 5-HT2A Receptor Antagonists in Medicinal Chemistry: A Last Decades Survey.

  2023cites this paper
• Molecular Dynamics-Based Allosteric Prediction Method to Design Key Residues in Threonine Dehydrogenase for Amino-Acid Production

  2021cites this paper
• Novel Positive Allosteric Modulators of µ Opioid Receptor—Insight from In Silico and In Vivo Studies

  2020influential citation
• Tuning Down the Pain - an Overview of Allosteric Modulation of Opioid Receptors: Mechanisms of Modulation, Allosteric Sites, Modulator Syntheses..

  2020cites this paper
• The role of water and protein flexibility in the structure-based virtual screening of allosteric GPCR modulators: an mGlu5 receptor case study

  2019cites this paper
• Metabolism

  2019cites this paper
• Receptor-Receptor Interactions as a Widespread Phenomenon: Novel Targets for Drug Development?

  2019cites this paper
• G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

  2018cites this paper
• Current Concepts and Treatments of Schizophrenia

  2018cites this paper
• Intracellular Receptor Modulation: Novel Approach to Target GPCRs.

  2018cites this paper