scholarly journals A Chemosensory GPCR as a Potential Target to Control the Root-Knot Nematode Meloidogyne incognita Parasitism in Plants

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3798 ◽  
Author(s):  
Emmanuel Bresso ◽  
Diana Fernandez ◽  
Deisy X. Amora ◽  
Philippe Noel ◽  
Anne-Sophie Petitot ◽  
...  
Keyword(s):  
Meloidogyne Incognita ◽  
Large Scale ◽  
3D Model ◽  
G Protein Coupled Receptors ◽  
Economic Damage ◽  
Root Knot Nematode ◽  
Worldwide Distribution ◽  
Starting Point ◽  
Dynamics Simulations ◽  
G Protein Coupled

Root-knot nematodes (RKN), from the Meloidogyne genus, have a worldwide distribution and cause severe economic damage to many life-sustaining crops. Because of their lack of specificity and danger to the environment, most chemical nematicides have been banned from use. Thus, there is a great need for new and safe compounds to control RKN. Such research involves identifying beforehand the nematode proteins essential to the invasion. Since G protein-coupled receptors GPCRs are the target of a large number of drugs, we have focused our research on the identification of putative nematode GPCRs such as those capable of controlling the movement of the parasite towards (or within) its host. A datamining procedure applied to the genome of Meloidogyne incognita allowed us to identify a GPCR, belonging to the neuropeptide GPCR family that can serve as a target to carry out a virtual screening campaign. We reconstructed a 3D model of this receptor by homology modeling and validated it through extensive molecular dynamics simulations. This model was used for large scale molecular dockings which produced a filtered limited set of putative antagonists for this GPCR. Preliminary experiments using these selected molecules allowed the identification of an active compound, namely C260-2124, from the ChemDiv provider, which can serve as a starting point for further investigations.

scholarly journals Constitutive signal bias mediated by the human GHRHR splice variant 1

2021 ◽  
Vol 118 (40) ◽  
pp. e2106606118
Author(s):  
Zhaotong Cong ◽  
Fulai Zhou ◽  
Chao Zhang ◽  
Xinyu Zou ◽  
Huibing Zhang ◽  
...  
Keyword(s):  
Splice Variant ◽  
Human Growth ◽  
Bound State ◽  
G Protein Coupled Receptors ◽  
Cancer Cell Proliferation ◽  
Downstream Signaling ◽  
Functional Studies ◽  
Dynamics Simulations ◽  
Protein Molecular Dynamics ◽  
G Protein Coupled

Alternative splicing of G protein–coupled receptors has been observed, but their functions are largely unknown. Here, we report that a splice variant (SV1) of the human growth hormone–releasing hormone receptor (GHRHR) is capable of transducing biased signal. Differing only at the receptor N terminus, GHRHR predominantly activates Gs while SV1 selectively couples to β-arrestins. Based on the cryogenic electron microscopy structures of SV1 in the apo state or GHRH-bound state in complex with the Gs protein, molecular dynamics simulations reveal that the N termini of GHRHR and SV1 differentiate the downstream signaling pathways, Gs versus β-arrestins. As suggested by mutagenesis and functional studies, it appears that GHRH-elicited signal bias toward β-arrestin recruitment is constitutively mediated by SV1. The level of SV1 expression in prostate cancer cells is also positively correlated with ERK1/2 phosphorylation but negatively correlated with cAMP response. Our findings imply that constitutive signal bias may be a mechanism that ensures cancer cell proliferation.

scholarly journals G Protein-Coupled Receptors Self-Assemble in Dynamics Simulations of Model Bilayers

2007 ◽  
Vol 129 (33) ◽  
pp. 10126-10132 ◽  
Author(s):  
Xavier Periole ◽  
Thomas Huber ◽  
Siewert-Jan Marrink ◽  
Thomas P. Sakmar
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Dynamics Simulations ◽  
G Protein Coupled

scholarly journals Development of OPLS-AA/M Parameters for Simulations of G Protein-Coupled Receptors and Other Membrane Proteins

2022 ◽  
Author(s):  
Michael J. Robertson ◽  
Georgios Skiniotis
Keyword(s):  
Membrane Proteins ◽  
Force Field ◽  
G Protein ◽  
Drug Targets ◽  
G Protein Coupled Receptors ◽  
Dynamic Nature ◽  
Post Translational Modifications ◽  
Dynamics Simulations ◽  
High Level ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) and other membrane proteins are valuable drug targets, and their dynamic nature makes them attractive systems for study with molecular dynamics simulations and free energy approaches. Here, we report the development, implementation, and validation of OPLS-AA/M force field parameters to enable simulations of these systems. These efforts include the introduction of post-translational modifications including lipidations and phosphorylation. We also modify previously reported parameters for lipids to be more consistent with the OPLS-AA force field standard and extend their coverage. These new parameters are validated on a variety of test systems, with the results compared to high-level quantum mechanics calculations, experimental data, and simulations with CHARMM36m where relevant. The results demonstrate that the new parameters reliably reproduce the behavior of membrane protein systems.

scholarly journals Differential Activation of P-TEFb Complexes in the Development of Cardiomyocyte Hypertrophy following Activation of Distinct G Protein-Coupled Receptors

2020 ◽  
Vol 40 (14) ◽  
Author(s):  
Ryan D. Martin ◽  
Yalin Sun ◽  
Sarah MacKinnon ◽  
Luca Cuccia ◽  
Viviane Pagé ◽  
...  
Keyword(s):  
Gene Expression ◽  
G Protein ◽  
Large Scale ◽  
Target Genes ◽  
G Protein Coupled Receptors ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Rat Cardiomyocytes ◽  
Brd4 Inhibition ◽  
G Protein Coupled

ABSTRACT Pathological cardiac hypertrophy is driven by neurohormonal activation of specific G protein-coupled receptors (GPCRs) in cardiomyocytes and is accompanied by large-scale changes in cardiomyocyte gene expression. These transcriptional changes require activity of positive transcription elongation factor b (P-TEFb), which is recruited to target genes by the bromodomain protein Brd4 or the super elongation complex (SEC). Here, we describe GPCR-specific regulation of these P-TEFb complexes and a novel mechanism for activating Brd4 in primary neonatal rat cardiomyocytes. The SEC was required for the hypertrophic response downstream of either the α1-adrenergic receptor (α1-AR) or the endothelin receptor (ETR). In contrast, Brd4 inhibition selectively impaired the α1-AR response. This was corroborated by the finding that the activation of α1-AR, but not ETR, increased Brd4 occupancy at promoters and superenhancers of hypertrophic genes. Transcriptome analysis demonstrated that the activation of both receptors initiated similar gene expression programs, but that Brd4 inhibition attenuated hypertrophic genes more robustly following α1-AR activation. Finally, we show that protein kinase A (PKA) is required for α1-AR stimulation of Brd4 chromatin occupancy. The differential role of the Brd4/P-TEFb complex in response to distinct GPCR pathways has potential clinical implications, as therapies targeting this complex are currently being explored for heart failure.

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