scholarly journals Novel Computational Methodologies for Structural Modeling of Spacious Ligand Binding Sites of G-Protein-Coupled Receptors: Development and Application to Human Leukotriene B4 Receptor

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Yoko Ishino ◽  
Takanori Harada
Keyword(s):  
G Protein ◽  
Time Scale ◽  
Thermal Fluctuations ◽  
Leukotriene B4 ◽  
G Protein Coupled Receptors ◽  
Dynamics Simulation ◽  
Ligand Docking ◽  
Leukotriene B4 Receptor ◽  
G Protein Coupled ◽  
Gpcr Protein

This paper describes a novel method to predict the activated structures of G-protein-coupled receptors (GPCRs) with high accuracy, while aiming for the use of the predicted 3D structures inin silicovirtual screening in the future. We propose a new method for modeling GPCR thermal fluctuations, where conformation changes of the proteins are modeled by combining fluctuations on multiple time scales. The core idea of the method is that a molecular dynamics simulation is used to calculate average 3D coordinates of all atoms of a GPCR protein against heat fluctuation on the picosecond or nanosecond time scale, and then evolutionary computation including receptor-ligand docking simulations functions to determine the rotation angle of each helix of a GPCR protein as a movement on a longer time scale. The method was validated using human leukotriene B4 receptor BLT1 as a sample GPCR. Our study demonstrated that the proposed method was able to derive the appropriate 3D structure of the active-state GPCR which docks with its agonists.

scholarly journals Assessment and Challenges of Ligand Docking into Comparative Models of G-Protein Coupled Receptors

PLoS ONE ◽  
2013 ◽  
Vol 8 (7) ◽  
pp. e67302 ◽  
Author(s):  
Elizabeth Dong Nguyen ◽  
Christoffer Norn ◽  
Thomas M. Frimurer ◽  
Jens Meiler
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Ligand Docking ◽  
G Protein Coupled

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.

scholarly journals Ligand Docking Methods to Recognize Allosteric Inhibitors for G-protein Coupled Receptors

2020 ◽  
Author(s):  
K Harini ◽  
S Jayashree ◽  
Vikas Tiwari ◽  
Sneha Vishwanath ◽  
Ramanathan Sowdhamini
Keyword(s):  
Binding Site ◽  
G Protein ◽  
Drug Targets ◽  
G Protein Coupled Receptors ◽  
Ligand Docking ◽  
Computational Docking ◽  
Cellular Processes ◽  
Activation Mechanisms ◽  
Approved Drugs ◽  
G Protein Coupled

G-protein coupled receptors (GPCRs) are large protein families known to be important in many cellular processes. They are well known for their allosteric activation mechanisms. They are drug targets for several FDA-approved drugs. We have investigated the diversity of the ligand binding site for these class of proteins against their cognate ligands using computational docking, even if their structures are known in the ligand-complexed form. The cognate ligand of some of these receptors dock at allosteric binding site, with better score than the binding at the conservative site. Further, ligands obtained from GLASS database, which consists of experimentally verified GPCR ligands, also show allosteric binding to GPCRs. The allosteric binders show strong affinity to the binding site, though the residues at the binding site are not conserved across GPCR subfamilies.

scholarly journals Ligand Docking Methods to Recognize Allosteric Inhibitors for G-Protein-Coupled Receptors

2021 ◽  
Vol 15 ◽  
pp. 117793222110377
Author(s):  
K Harini ◽  
S Jayashree ◽  
Vikas Tiwari ◽  
Sneha Vishwanath ◽  
Ramanathan Sowdhamini
Keyword(s):  
Binding Site ◽  
G Protein ◽  
Drug Targets ◽  
Drug Binding ◽  
G Protein Coupled Receptors ◽  
Ligand Docking ◽  
Amino Acid Residues ◽  
Computational Docking ◽  
Cellular Processes ◽  
G Protein Coupled

G-protein-coupled receptors (GPCRs) are membrane proteins which play an important role in many cellular processes and are excellent drug targets. Despite the existence of several US Food and Drug Administration (FDA)-approved GPCR-targeting drugs, there is a continuing challenge of side effects owing to the nonspecific nature of drug binding. We have investigated the diversity of the ligand binding site for this class of proteins against their cognate ligands using computational docking, even if their structures are known already in the ligand-complexed form. The cognate ligand of some of these receptors dock at allosteric binding site with better score than the binding at the conservative site. Interestingly, amino acid residues at such allosteric binding site are not conserved across GPCR subfamilies. Such a computational approach can assist in the prediction of specific allosteric binders for GPCRs.

scholarly journals patGPCR: A Multitemplate Approach for Improving 3D Structure Prediction of Transmembrane Helices of G-Protein-Coupled Receptors

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Hongjie Wu ◽  
Qiang Lü ◽  
Lijun Quan ◽  
Peide Qian ◽  
Xiaoyan Xia
Keyword(s):  
G Protein ◽  
Structure Prediction ◽  
Transmembrane Helix ◽  
3D Structure ◽  
G Protein Coupled Receptors ◽  
Ligand Docking ◽  
Molecular Function ◽  
Transmembrane Helices ◽  
G Protein Coupled ◽  
Multiple Template

The structures of the seven transmembrane helices of G-protein-coupled receptors are critically involved in many aspects of these receptors, such as receptor stability, ligand docking, and molecular function. Most of the previous multitemplate approaches have built a “super” template with very little merging of aligned fragments from different templates. Here, we present a parallelized multitemplate approach, patGPCR, to predict the 3D structures of transmembrane helices of G-protein-coupled receptors. patGPCR, which employs a bundle-packing related energy function that extends on the RosettaMem energy, parallelizes eight pipelines for transmembrane helix refinement and exchanges the optimized helix structures from multiple templates. We have investigated the performance of patGPCR on a test set containing eight determined G-protein-coupled receptors. The results indicate that patGPCR improves the TM RMSD of the predicted models by 33.64% on average against a single-template method. Compared with other homology approaches, the best models for five of the eight targets built by patGPCR had a lower TM RMSD than that obtained from SWISS-MODEL; patGPCR also showed lower average TM RMSD than single-template and multiple-template MODELLER.

scholarly journals A complex structure of arrestin-2 bound to a G protein-coupled receptor

2019 ◽  
Author(s):  
Wanchao Yin ◽  
Zhihai Li ◽  
Mingliang Jin ◽  
Yu-Ling Yin ◽  
Parker W. de Waal ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
G Protein ◽  
Complex Structure ◽  
Transmembrane Helix ◽  
G Protein Coupled Receptors ◽  
Dynamics Simulation ◽  
Intracellular Loop ◽  
Neurotensin Receptor 1 ◽  
G Protein Coupled

AbstractArrestins comprise a family of signal regulators of G-protein-coupled receptors (GPCRs), which include arrestins 1 to 4. While arrestins 1 and 4 are visual arrestins dedicated to rhodopsin, arrestins 2 and 3 (Arr2 and Arr3) are β-arrestins known to regulate many nonvisual GPCRs. The dynamic and promiscuous coupling of Arr2 to nonvisual GPCRs has posed technical challenges to tackle the basis of arrestin binding to GPCRs. Here we report the structure of Arr2 in complex with neurotensin receptor 1 (NTSR1), which reveals an overall assembly that is strikingly different from the visual arrestin-rhodopsin complex by a 90° rotation of Arr2 relative to the receptor. In this new configuration, intracellular loop 3 (ICL3) and transmembrane helix 6 (TM6) of the receptor are oriented toward the N-terminal domain of the arrestin, making it possible for GPCRs that lack the C-terminal tail to couple Arr2 through their ICL3. Molecular dynamics simulation and crosslinking data further support the assembly of the Arr2–NTSR1 complex. Sequence analysis and homology modeling suggest that the Arr2–NTSR1 complex structure may provide an alternative template for modeling arrestin-GPCR interactions.

scholarly journals Pathological AT1R-B2R Protein Aggregation and Preeclampsia

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2609
Author(s):  
Ursula Quitterer ◽  
Said AbdAlla
Keyword(s):  
Risk Factors ◽  
Complex Formation ◽  
Protein Aggregation ◽  
G Protein ◽  
Protein Complex ◽  
G Protein Coupled Receptors ◽  
Protein Complex Formation ◽  
The Impact ◽  
G Protein Coupled ◽  
Gpcr Protein

Preeclampsia is one of the most frequent and severe complications of pregnancy. Symptoms of preeclampsia usually occur after 20 weeks of pregnancy and include hypertension and kidney dysfunction with proteinuria. Up to now, delivery of the infant has been the most effective and life-saving treatment to alleviate symptoms of preeclampsia because a causative treatment does not exist, which could prolong a pregnancy complicated with preeclampsia. Preeclampsia is a complex medical condition, which is attributed to a variety of different risk factors and causes. Risk factors account for insufficient placentation and impaired vasculogenesis and finally culminate in this life-threatening condition of pregnancy. Despite progress, many pathomechanisms and causes of preeclampsia are still incompletely understood. In recent years, it was found that excessive protein complex formation between G-protein-coupled receptors is a common sign of preeclampsia. Specifically, the aberrant heteromerization of two vasoactive G-protein-coupled receptors (GPCRs), the angiotensin II AT1 receptor and the bradykinin B2 receptor, is a causative factor of preeclampsia symptoms. Based on this knowledge, inhibition of abnormal GPCR protein complex formation is an experimental treatment approach of preeclampsia. This review summarizes the impact of pathological GPCR protein aggregation on symptoms of preeclampsia and delineates potential new therapeutic targets.

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