The nociceptin receptor (NOPR) and its interaction with clinically important agonist molecules: a membrane molecular dynamics simulation study

2014 ◽  
Vol 10 (12) ◽  
pp. 3188-3198 ◽  
Author(s):  
Gugan Kothandan ◽  
Changdev G. Gadhe ◽  
Anand Balupuri ◽  
Jagadeesan Ganapathy ◽  
Seung Joo Cho
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
G Protein ◽  
Simulation Study ◽  
Dynamics Simulation ◽  
Transmembrane Helices ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled ◽  
Nociceptin Receptor

The nociceptin receptor (NOPR) is an orphan G protein-coupled receptor that contains seven transmembrane helices.

scholarly journals Computational Investigations on the Binding Mode of Ligands for the Cannabinoid-Activated G Protein-Coupled Receptor GPR18

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 686 ◽  
Author(s):  
Alexander Neumann ◽  
Viktor Engel ◽  
Andhika B. Mahardhika ◽  
Clara T. Schoeder ◽  
Vigneshwaran Namasivayam ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
G Protein ◽  
Phenyl Ring ◽  
Binding Mode ◽  
Dynamics Simulation ◽  
Simulation Studies ◽  
Binding Modes ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

GPR18 is an orphan G protein-coupled receptor (GPCR) expressed in cells of the immune system. It is activated by the cannabinoid receptor (CB) agonist ∆9-tetrahydrocannabinol (THC). Several further lipids have been proposed to act as GPR18 agonists, but these results still require unambiguous confirmation. In the present study, we constructed a homology model of the human GPR18 based on an ensemble of three GPCR crystal structures to investigate the binding modes of the agonist THC and the recently reported antagonists which feature an imidazothiazinone core to which a (substituted) phenyl ring is connected via a lipophilic linker. Docking and molecular dynamics simulation studies were performed. As a result, a hydrophobic binding pocket is predicted to accommodate the imidazothiazinone core, while the terminal phenyl ring projects towards an aromatic pocket. Hydrophobic interaction of Cys251 with substituents on the phenyl ring could explain the high potency of the most potent derivatives. Molecular dynamics simulation studies suggest that the binding of imidazothiazinone antagonists stabilizes transmembrane regions TM1, TM6 and TM7 of the receptor through a salt bridge between Asp118 and Lys133. The agonist THC is presumed to bind differently to GPR18 than to the distantly related CB receptors. This study provides insights into the binding mode of GPR18 agonists and antagonists which will facilitate future drug design for this promising potential drug target.

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.

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