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

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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An Efficient Molecular Dynamics Simulation Strategy to Investigate the Mechanistic Basis for Biased Agonism at G Protein-Coupled Receptors

Biophysical Journal ◽

10.1016/j.bpj.2017.11.1129 ◽

2018 ◽

Vol 114 (3) ◽

pp. 202a

Author(s):

Derya Meral ◽

Davide Provasi ◽

Marta Filizola

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulation ◽

G Protein ◽

G Protein Coupled Receptors ◽

Dynamics Simulation ◽

Biased Agonism ◽

Simulation Strategy ◽

Mechanistic Basis ◽

G Protein Coupled

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G-Protein/β-Arrestin-Linked Fluctuating Network of G-Protein-Coupled Receptors for Predicting Drug Efficacy and Bias Using Short-Term Molecular Dynamics Simulation

PLoS ONE ◽

10.1371/journal.pone.0155816 ◽

2016 ◽

Vol 11 (5) ◽

pp. e0155816 ◽

Cited By ~ 5

Author(s):

Osamu Ichikawa ◽

Kazushi Fujimoto ◽

Atsushi Yamada ◽

Susumu Okazaki ◽

Kazuto Yamazaki

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulation ◽

G Protein ◽

Drug Efficacy ◽

G Protein Coupled Receptors ◽

Dynamics Simulation ◽

Short Term ◽

G Protein Coupled

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

Biomolecules ◽

10.3390/biom10050686 ◽

2020 ◽

Vol 10 (5) ◽

pp. 686 ◽

Cited By ~ 3

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.

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The Role of ICL1 and H8 in Class B1 GPCRs; Implications for Receptor Activlation

Frontiers in Endocrinology ◽

10.3389/fendo.2021.792912 ◽

2022 ◽

Vol 12 ◽

Author(s):

Ian Winfield ◽

Kerry Barkan ◽

Sarah Routledge ◽

Nathan J. Robertson ◽

Matthew Harris ◽

...

Keyword(s):

Molecular Dynamics ◽

G Protein ◽

Conformational Changes ◽

Transmembrane Helix ◽

Receptor Activation ◽

Cgrp Receptor ◽

Intracellular Loop ◽

Glucagon Receptor ◽

G Protein Coupled

The first intracellular loop (ICL1) of G protein-coupled receptors (GPCRs) has received little attention, although there is evidence that, with the 8th helix (H8), it is involved in early conformational changes following receptor activation as well as contacting the G protein β subunit. In class B1 GPCRs, the distal part of ICL1 contains a conserved R12.48KLRCxR2.46b motif that extends into the base of the second transmembrane helix; this is weakly conserved as a [R/H]12.48KL[R/H] motif in class A GPCRs. In the current study, the role of ICL1 and H8 in signaling through cAMP, iCa2+ and ERK1/2 has been examined in two class B1 GPCRs, using mutagenesis and molecular dynamics. Mutations throughout ICL1 can either enhance or disrupt cAMP production by CGRP at the CGRP receptor. Alanine mutagenesis identified subtle differences with regard elevation of iCa2+, with the distal end of the loop being particularly sensitive. ERK1/2 activation displayed little sensitivity to ICL1 mutation. A broadly similar pattern was observed with the glucagon receptor, although there were differences in significance of individual residues. Extending the study revealed that at the CRF1 receptor, an insertion in ICL1 switched signaling bias between iCa2+ and cAMP. Molecular dynamics suggested that changes in ICL1 altered the conformation of ICL2 and the H8/TM7 junction (ICL4). For H8, alanine mutagenesis showed the importance of E3908.49b for all three signal transduction pathways, for the CGRP receptor, but mutations of other residues largely just altered ERK1/2 activation. Thus, ICL1 may modulate GPCR bias via interactions with ICL2, ICL4 and the Gβ subunit.

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