scholarly journals Molecular basis for lipid recognition by the prostaglandin D2 receptor CRTH2

2021 ◽  
Vol 118 (32) ◽  
pp. e2102813118
Author(s):  
Heng Liu ◽  
R. N. V. Krishna Deepak ◽  
Anna Shiriaeva ◽  
Cornelius Gati ◽  
Alexander Batyuk ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
D2 Receptor ◽  
Binding Mode ◽  
Lipid Binding ◽  
Prostaglandin D2 ◽  
Polar Group ◽  
Binding Modes ◽  
Binding Pockets ◽  
Dynamics Simulations ◽  
G Protein Coupled

Prostaglandin D2 (PGD2) signals through the G protein–coupled receptor (GPCR) CRTH2 to mediate various inflammatory responses. CRTH2 is the only member of the prostanoid receptor family that is phylogenetically distant from others, implying a nonconserved mechanism of lipid action on CRTH2. Here, we report a crystal structure of human CRTH2 bound to a PGD2 derivative, 15R-methyl-PGD2 (15mPGD2), by serial femtosecond crystallography. The structure revealed a “polar group in”–binding mode of 15mPGD2 contrasting the “polar group out”–binding mode of PGE2 in its receptor EP3. Structural comparison analysis suggested that these two lipid-binding modes, associated with distinct charge distributions of ligand-binding pockets, may apply to other lipid GPCRs. Molecular dynamics simulations together with mutagenesis studies also identified charged residues at the ligand entry port that function to capture lipid ligands of CRTH2 from the lipid bilayer. Together, our studies suggest critical roles of charge environment in lipid recognition by GPCRs.

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 Flavonoids as Putative Epi-Modulators: Insight into Their Binding Mode with BRD4 Bromodomains Using Molecular Docking and Dynamics

Biomolecules ◽  
2018 ◽  
Vol 8 (3) ◽  
pp. 61 ◽  
Author(s):  
Fernando Prieto-Martínez ◽  
José Medina-Franco
Keyword(s):  
Kinase Inhibitors ◽  
Binding Mode ◽  
Binding Modes ◽  
Ligand Interaction ◽  
Bet Inhibitors ◽  
Protein Ligand Interaction ◽  
Brd4 Inhibition ◽  
Dynamics Simulations ◽  
Insight Into

Flavonoids are widely recognized as natural polydrugs, given their anti-inflammatory, antioxidant, sedative, and antineoplastic activities. Recently, different studies showed that flavonoids have the potential to inhibit bromodomain and extraterminal (BET) bromodomains. Previous reports suggested that flavonoids bind between the Z and A loops of the bromodomain (ZA channel) due to their orientation and interactions with P86, V87, L92, L94, and N140. Herein, a comprehensive characterization of the binding modes of fisetin and the biflavonoid, amentoflavone, is discussed. To this end, both compounds were docked with BET bromodomain 4 (BRD4) using four docking programs. The results were post-processed with protein–ligand interaction fingerprints. To gain further insight into the binding mode of the two natural products, the docking results were further analyzed with molecular dynamics simulations. The results showed that amentoflavone makes numerous contacts in the ZA channel, as previously described for flavonoids and kinase inhibitors. It was also found that amentoflavone can potentially make contacts with non-canonical residues for BET inhibition. Most of these contacts were not observed with fisetin. Based on these results, amentoflavone was experimentally tested for BRD4 inhibition, showing activity in the micromolar range. This work may serve as the basis for scaffold optimization and the further characterization of flavonoids as BET inhibitors.

scholarly journals Deciphering the Agonist Binding Mechanism to the Adenosine A1 Receptor

2020 ◽  
Author(s):  
Giuseppe Deganutti ◽  
Kerry Barkan ◽  
Barbara Preti ◽  
Michele Leuenberger ◽  
Mark Wall ◽  
...  
Keyword(s):  
Drug Design ◽  
Binding Mode ◽  
Adenosine A1 Receptor ◽  
Dissociation Pathway ◽  
Binding Mechanism ◽  
Structure Based Drug Design ◽  
Adenosine A1 ◽  
A1 Receptor ◽  
Dynamics Simulations ◽  
G Protein Coupled

ABSTRACTDespite being amongst the most characterized G protein-coupled receptors (GPCRs), adenosine receptors (ARs) have always been a difficult target in drug design. To date, no agonist other than the natural effector and the diagnostic regadenoson has been approved for human use. Recently, the structure of the adenosine A1 receptor (A1R) was determined in the active, Gi protein complexed state; this has important repercussions for structure-based drug design. Here, we employed supervised molecular dynamics simulations and mutagenesis experiments to extend the structural knowledge of the binding of selective agonists to A1R. Our results identify new residues involved in the association and dissociation pathway, suggest the binding mode of N6-cyclopentyladenosine (CPA) related ligands, and highlight the dramatic effect that chemical modifications can have on the overall binding mechanism.

scholarly journals Evidence for Two Modes of Binding of the Negative Allosteric Modulator SB269,652 to the Dopamine D2 Receptor

Biomedicines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 22
Author(s):  
Richard Ågren ◽  
Kristoffer Sahlholm
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Binding Pocket ◽  
Binding Mode ◽  
Allosteric Modulator ◽  
Drug Candidates ◽  
Dopamine D2 ◽  
Inward Rectifier Potassium Channels ◽  
Negative Allosteric Modulator ◽  
G Protein Coupled

SB269,652 has been described as the first negative allosteric modulator (NAM) of the dopamine D2 receptor (D2R), however, the binding mode and allosteric mechanism of action of this ligand remain incompletely understood. SB269,652 comprises an orthosteric, primary pharmacophore and a secondary (or allosteric) pharmacophore joined by a hydrophilic cyclohexyl linker and is known to form corresponding interactions with the orthosteric binding site (OBS) and the secondary binding pocket (SBP) in the D2R. Here, we observed a surprisingly low potency of SB269,652 to negatively modulate the D2R-mediated activation of G protein-coupled inward-rectifier potassium channels (GIRK) and decided to perform a more detailed investigation of the interaction between dopamine and SB269,652. The results indicated that the SB269,652 inhibitory potency is increased 6.6-fold upon ligand pre-incubation, compared to the simultaneous co-application with dopamine. Mutagenesis experiments implicated both S193 in the OBS and E95 in the SBP in the effect of pre-application. The present findings extend previous knowledge about how SB269,652 competes with dopamine at the D2R and may be useful for the development of novel D2R ligands, such as antipsychotic drug candidates.

scholarly journals DFG-1 residue controls inhibitor binding mode and affinity providing a basis for rational design of kinase inhibitor selectivity

2020 ◽  
Author(s):  
Martin Schröder ◽  
Alex N. Bullock ◽  
Oleg Federov ◽  
Franz Bracher ◽  
Apirat Chaikuad ◽  
...  
Keyword(s):  
Rational Design ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Binding Mode ◽  
Selectivity Filter ◽  
Binding Modes ◽  
Selective Inhibitors ◽  
Inhibitor Binding ◽  
Binding Pockets ◽  
Inhibitor Selectivity

ABSTRACTSelectivity remains a challenge for ATP-mimetic kinase inhibitors, an issue that may be overcome by targeting unique residues or binding pockets. However, to date only few strategies have been developed. Here we identify that bulky residues located N-terminal to the DFG motif (DFG-1) represent an opportunity for designing highly selective inhibitors with unexpected binding modes. We demonstrate that several diverse inhibitors exerted selective, non-canonical binding modes that exclusively target large hydrophobic DFG-1 residues present in many kinases including PIM, CK1, DAPK and CLK. Using the CLK family as a model, structural and biochemical data revealed that the DFG-1 valine controlled a non-canonical binding mode in CLK1, providing a rational for selectivity over the closely-related CLK3 which harbors a smaller DFG-1 alanine. Our data suggests that targeting the restricted back pocket in the small fraction of kinases that harbor bulky DFG-1 residues offers a versatile selectivity filter for inhibitor design.

scholarly journals Structural Effects of Cation Binding to DPPC Monolayers

2020 ◽  
Author(s):  
Matti Javanainen ◽  
Wei Hua ◽  
Ondrej Tichacek ◽  
Pauline Delcroix ◽  
Lukasz Cwiklik ◽  
...  
Keyword(s):  
Radical Change ◽  
Binding Mode ◽  
Cation Binding ◽  
Head Group ◽  
Binding Modes ◽  
Sum Frequency ◽  
Area Per Lipid ◽  
Simulation And Experiment ◽  
Lipid Head Group ◽  
Dynamics Simulations

Ions at the two sides of the plasma membrane maintain the transmembrane potential, participate in signaling, and affect the properties of the membrane itself. The extracellular leaflet is particularly enriched in phosphatidylcholine lipids an under the influence of Na+, Ca2+, and Cl− ions. In this work, we combined molecular dynamics simulations performed using state-of-the-art models with vibrational sum frequency generation (VSFG) spectroscopy to study the effects of these key ions on the structure of dipalmitoylphosphatidylcholine. We used lipid monolayers as a proxy for membranes, as this approach enabled a direct comparison between simulation and experiment. We find that the effects of Na+ are minor. Ca2+, on the other hand, strongly affects the lipid head group conformations and induces a tighter packing of lipids, thus promoting the liquid condensed phase. It does so by binding to both the phosphate and carbonyl oxygens via direct and water-mediated binding modes, the ratios of which depend on the monolayer packing. Clustering analysis performed on simulation data revealed that changes in area per lipid or CaCl2 concentration both affect the head group conformations, yet their effects are anti-correlated. Cations at the monolayer surface also attract Cl−, which at large CaCl2 concentrations penetrates deep to the monolayer. This phenomenon coincides with a radical change in the VSFG spectra of the phosphate group, thus indicating the emergence of a new binding mode.

scholarly journals Impact of membrane lipid polyunsaturation on dopamine D2 receptor ligand binding and signaling

2022 ◽  
Author(s):  
Marie-Lise Jobin ◽  
Veronique De Smedt-Peyrusse ◽  
Fabien Ducrocq ◽  
Asma Oummadi ◽  
Rim Baccouch ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Dopamine D2 Receptor ◽  
Second Messengers ◽  
D2 Receptor ◽  
Membrane Lipid ◽  
Allosteric Modulators ◽  
Dopamine D2 ◽  
Dynamics Simulations ◽  
G Protein Coupled

The heterogenous and dynamic constitution of the membrane fine-tunes signal transduction. In particular, the polyunsaturated fatty acid (PUFA) tails of phospholipids influence the biophysical properties of the membrane, production of second messengers, or membrane partitioning. Few evidence mostly originating from studies of rhodopsin suggest that PUFAs directly modulate the conformational dynamic of transmembrane proteins. However, whether such properties translate to other G protein-coupled receptors remains unclear. We focused on the dopamine D2 receptor (D2R), a main target of antipsychotics. Membrane enrichment in n-3, but not n-6, PUFAs potentiates ligand binding. Molecular dynamics simulations show that the D2R preferentially interacts with n-3 over n-6 PUFAs. Furthermore, even though this mildly affects signalling in heterologous systems, in vivo n-3 PUFA deficiency blunts the effects of D2R ligands. These results suggest that n-3 PUFAs act as allosteric modulators of the D2R and provide a putative mechanism for their potentiating effect on antipsychotic efficacy.

scholarly journals Structural Effects of Cation Binding to DPPC Monolayers

2020 ◽  
Author(s):  
Matti Javanainen ◽  
Wei Hua ◽  
Ondrej Tichacek ◽  
Pauline Delcroix ◽  
Lukasz Cwiklik ◽  
...  
Keyword(s):  
Radical Change ◽  
Binding Mode ◽  
Cation Binding ◽  
Head Group ◽  
Binding Modes ◽  
Sum Frequency ◽  
Area Per Lipid ◽  
Simulation And Experiment ◽  
Lipid Head Group ◽  
Dynamics Simulations

Ions at the two sides of the plasma membrane maintain the transmembrane potential, participate in signaling, and affect the properties of the membrane itself. The extracellular leaflet is particularly enriched in phosphatidylcholine lipids an under the influence of Na+, Ca2+, and Cl− ions. In this work, we combined molecular dynamics simulations performed using state-of-the-art models with vibrational sum frequency generation (VSFG) spectroscopy to study the effects of these key ions on the structure of dipalmitoylphosphatidylcholine. We used lipid monolayers as a proxy for membranes, as this approach enabled a direct comparison between simulation and experiment. We find that the effects of Na+ are minor. Ca2+, on the other hand, strongly affects the lipid head group conformations and induces a tighter packing of lipids, thus promoting the liquid condensed phase. It does so by binding to both the phosphate and carbonyl oxygens via direct and water-mediated binding modes, the ratios of which depend on the monolayer packing. Clustering analysis performed on simulation data revealed that changes in area per lipid or CaCl2 concentration both affect the head group conformations, yet their effects are anti-correlated. Cations at the monolayer surface also attract Cl−, which at large CaCl2 concentrations penetrates deep to the monolayer. This phenomenon coincides with a radical change in the VSFG spectra of the phosphate group, thus indicating the emergence of a new binding mode.

scholarly journals Autonomous sensing the insulin peptide by an olfactory G protein coupled receptor modulates glucose metabolism

2020 ◽  
Author(s):  
Jie Cheng ◽  
Zhao Yang ◽  
Xiao-Yan Ge ◽  
Ming-Xin Gao ◽  
Ran Meng ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Homeostasis ◽  
Inflammatory Responses ◽  
Functional Characterization ◽  
Olfactory Receptors ◽  
Binding Mode ◽  
Obese Mouse ◽  
Β Cells ◽  
Islet Inflammation ◽  
G Protein Coupled

Along with functionally intact insulin, diabetes-associated insulin peptides are secreted by β cells(1-3). By screening the expression and functional characterization of olfactory receptors in pancreatic islets, we identified Olfr109 as the receptor to detect insulin peptides. Engagement of one insulin peptide, insB:9-23, with Olfr109 diminished insulin secretion through Gi-cAMP signalling and promoted macrophage proliferation. Remarkably, Olfr109 deficiency alleviated intra-islet inflammatory responses and improved glucose homeostasis in Akita- and HFD-fed mice. We further determined the binding mode between the insB:9-23 and Olfr109. A pepducin-based Olfr109 antagonist improved glucose homeostasis in diabetic and obese mouse models. Collectively, we found that pancreatic β cells use Olfr109 to autonomously detect self-secreted insulin peptides and this detection arrests insulin secretion and crosstalk with macrophages to increase intra-islet inflammation.

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