scholarly journals Automated Identification of Cholesterol Interaction Sites on G-Protein Coupled Receptors by Coarse-Grained Simulation

2017 ◽  
Vol 112 (3) ◽  
pp. 392a
Author(s):  
Eric Rouviere ◽  
Cément Arnarez ◽  
Edward Lyman
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Coarse Grained ◽  
Automated Identification ◽  
Interaction Sites ◽  
G Protein Coupled

Structure network analysis to gain insights into GPCR function

2016 ◽  
Vol 44 (2) ◽  
pp. 613-618 ◽  
Author(s):  
Francesca Fanelli ◽  
Angelo Felline ◽  
Francesco Raimondi ◽  
Michele Seeber
Keyword(s):  
G Protein ◽  
Normal Mode Analysis ◽  
Network Models ◽  
Md Simulations ◽  
G Protein Coupled Receptors ◽  
Coarse Grained ◽  
Mode Analysis ◽  
Biomolecular Systems ◽  
Retinal Chromophore ◽  
G Protein Coupled

G protein coupled receptors (GPCRs) are allosteric proteins whose functioning fundamentals are the communication between the two poles of the helix bundle. Protein structure network (PSN) analysis is one of the graph theory-based approaches currently used to investigate the structural communication in biomolecular systems. Information on system's dynamics can be provided by atomistic molecular dynamics (MD) simulations or coarse grained elastic network models paired with normal mode analysis (ENM–NMA). The present review article describes the application of PSN analysis to uncover the structural communication in G protein coupled receptors (GPCRs). Strategies to highlight changes in structural communication upon misfolding, dimerization and activation are described. Focus is put on the ENM–NMA-based strategy applied to the crystallographic structures of rhodopsin in its inactive (dark) and signalling active (meta II (MII)) states, highlighting changes in structure network and centrality of the retinal chromophore in differentiating the inactive and active states of the receptor.

scholarly journals Activation of G-protein coupled receptors is thermodynamically linked to lipid solvation

2020 ◽  
Author(s):  
Alison N. Leonard ◽  
Edward Lyman
Keyword(s):  
G Protein ◽  
Chemical Potential ◽  
Solvation Shell ◽  
G Protein Coupled Receptors ◽  
Dynamics Simulation ◽  
Coarse Grained ◽  
Unsaturated Lipids ◽  
Bulk Membrane ◽  
Enthalpy And Entropy ◽  
G Protein Coupled

AbstractPreferential lipid solvation of the G-protein coupled A2A adenosine receptor (A2AR) is evaluated from 35 μsec of all-atom molecular dynamics simulation. A coarse-grained transition matrix algorithm is developed to overcome slow equilibration of the first solvation shell, obtaining statistically robust estimates of the free energy of solvation by different lipids for the receptor in different activation states. Results indicate preference for solvation by unsaturated chains, which favors the active receptor. A model for lipid-dependent GPCR activity is proposed in which the chemical potential of lipids in the bulk membrane modulates receptor activity. The enthalpy and entropy associated with moving saturated vs. unsaturated lipids from bulk to A2AR’s first solvation shell are compared. In the simulated mixture, saturated chains are disordered (i.e., obtain a favorable entropic contribution) when partitioning to the receptor surface, but this is outweighed by a favorable enthalpic contribution for unsaturated chains to occupy the first solvation shell.

Ligand Pose Predictions for Human G Protein-Coupled Receptors: Insights from the Amber-Based Hybrid Molecular Mechanics/Coarse-Grained Approach

2020 ◽  
Vol 60 (10) ◽  
pp. 5103-5116 ◽  
Author(s):  
Jakob Schneider ◽  
Ksenia Korshunova ◽  
Zeineb Si Chaib ◽  
Alejandro Giorgetti ◽  
Mercedes Alfonso-Prieto ◽  
...  
Keyword(s):  
Molecular Mechanics ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Coarse Grained ◽  
G Protein Coupled

The third extracellular loop of G-protein-coupled receptors: more than just a linker between two important transmembrane helices

2004 ◽  
Vol 32 (6) ◽  
pp. 1048-1050 ◽  
Author(s):  
Z. Lawson ◽  
M. Wheatley
Keyword(s):  
G Protein ◽  
Tertiary Structure ◽  
Large Family ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Transmembrane Helices ◽  
Ligand Selectivity ◽  
Interaction Sites ◽  
Amine Neurotransmitters ◽  
G Protein Coupled

GPCRs (G-protein-coupled receptors) are a large family of structurally related proteins, which mediate their effects by coupling with G-proteins. Despite responding to a range of very diverse stimuli, these receptors exhibit a conserved tertiary structure comprising a bundle of seven TM (transmembrane) helices linked by alternating ECLs (extracellular loops) and ICLs (intracellular loops). The hydrophobic environment formed by the cluster of TM helices is functionally important. For example, the 11-cis retinal chromophore of rhodopsin forms a protonated Schiff base linkage to a lysine in TM7, deep within the helical bundle, and small ligands, such as amine neurotransmitters and non-peptide analogues of peptide hormones, also bind within the corresponding region of their cognate receptors. In addition, activation of GPCRs involves relative movement of TM helices to present G-protein interaction sites across the intracellular face of the receptor. Consequently, it might be assumed that the ECLs of the GPCR are inert peptide linkers that merely connect important TM helices. Focusing on ECL3 (third ECL), it is becoming increasingly apparent that this extracellular domain can fulfil a range of important roles with respect to GPCR signalling, including agonist binding, ligand selectivity and receptor activation.

Arrestin-dependent internalization of rhodopsin-like G protein-coupled receptors

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Lizzy Wanka ◽  
Victoria Behr ◽  
Annette G. Beck-Sickinger
Keyword(s):  
G Protein ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Emotional Behavior ◽  
Model Systems ◽  
Regulation Mechanism ◽  
Interaction Sites ◽  
Internalization Process ◽  
G Protein Coupled ◽  
Receptor Family

Abstract The internalization of G protein-coupled receptors (GPCRs) is an important mechanism regulating the signal strength and limiting the opportunity of receptor activation. Based on the importance of GPCRs, the detailed knowledge about the regulation of signal transduction is crucial. Here, current knowledge about the agonist-induced, arrestin-dependent internalization process of rhodopsin-like GPCRs is reviewed. Arrestins are conserved molecules that act as key players within the internalization process of many GPCRs. Based on highly conserved structural characteristics within the rhodopsin-like GPCRs, the identification of arrestin interaction sites in model systems can be compared and used for the investigation of internalization processes of other receptors. The increasing understanding of this essential regulation mechanism of receptors can be used for drug development targeting rhodopsin-like GPCRs. Here, we focus on the neuropeptide Y receptor family, as these receptors transmit various physiological processes such as food intake, energy homeostasis, and regulation of emotional behavior, and are further involved in pathophysiological processes like cancer, obesity and mood disorders. Hence, this receptor family represents an interesting target for the development of novel therapeutics requiring the understanding of the regulatory mechanisms influencing receptor mediated signaling.

Coarse-Grained Prediction of Peptide Binding to G-Protein Coupled Receptors

2017 ◽  
Vol 57 (3) ◽  
pp. 562-571 ◽  
Author(s):  
Bartholomé Delort ◽  
Pedro Renault ◽  
Landry Charlier ◽  
Florent Raussin ◽  
Jean Martinez ◽  
...  
Keyword(s):  
G Protein ◽  
Peptide Binding ◽  
G Protein Coupled Receptors ◽  
Coarse Grained ◽  
G Protein Coupled

Lipid-Dependent Regulation of Ion Channels and G Protein–Coupled Receptors: Insights from Structures and Simulations

2020 ◽  
Vol 60 (1) ◽  
pp. 31-50 ◽  
Author(s):  
Anna L. Duncan ◽  
Wanling Song ◽  
Mark S.P. Sansom
Keyword(s):  
Ion Channels ◽  
G Protein ◽  
Binding Sites ◽  
Trp Channels ◽  
Protein Structures ◽  
Lipid Binding ◽  
G Protein Coupled Receptors ◽  
Interaction Sites ◽  
Lipid Sensor ◽  
G Protein Coupled

Ion channels and G protein–coupled receptors (GPCRs) are regulated by lipids in their membrane environment. Structural studies combined with biophysical and molecular simulation investigations reveal interaction sites for specific lipids on membrane protein structures. For K channels, PIP2 plays a key role in regulating Kv and Kir channels. Likewise, several recent cryo-EM structures of TRP channels have revealed bound lipids, including PIP2 and cholesterol. Among the pentameric ligand-gated ion channel family, structural and biophysical studies suggest the M4 TM helix may act as a lipid sensor, e.g., forming part of the binding sites for neurosteroids on the GABAA receptor. Structures of GPCRs have revealed multiple cholesterol sites, which may modulate both receptor dynamics and receptor oligomerization. PIP2 also interacts with GPCRs and may modulate their interactions with G proteins. Overall, it is evident that multiple lipid binding sites exist on channels and receptors that modulate their function allosterically and are potential druggable sites.

Sign in / Sign up

Export Citation Format

Share Document