scholarly journals Structure-guided optimization of light-activated chimeric G-protein coupled receptors

2021 ◽  
Author(s):  
Alexandra-Madelaine Tichy ◽  
Wang Lok So ◽  
Elliot Gerrard ◽  
Harald Janovjak
Keyword(s):  
G Protein ◽  
Protein Complexes ◽  
G Protein Coupled Receptors ◽  
Design Strategies ◽  
Core Domain ◽  
Chimeric Receptors ◽  
Downstream Signaling ◽  
Rational Engineering ◽  
G Protein Coupled ◽  
Receptor Family

G-protein coupled receptors (GPCRs) are the largest human receptor family and involved in virtually every physiological process. One hallmark of GPCR function is the specific coupling of activated receptors to selected downstream signaling pathways. The ability to tune this coupling would permit the development of receptors with new capabilities. GPCRs and G-proteins have been recently resolved structurally at high resolution, but this information was in only very few cases harnessed for a rational engineering of these protein complexes. Here, we demonstrate the structure-guided optimization of coupling in chimeric light-activated GPCRs (OptoXRs). Our hypothesis was that the incorporation of structural GPCR-Gα contacts will lead to improved receptor activity. We first evaluated structure-based alignments as complements to existing sequence-based methods for generation of chimeric receptors. We then show in a prototypical light-activated β2AR that inclusion of α-helical residues forming structural contacts to Gα resulted in receptors with 7- to 20-fold increased function compared to other design strategies. In turn, elimination of GPCR-Gα contacts diminished function. Finally, the efficient receptor design served as a platform for the optimization of a further light-activated receptor and spectral tuning of the photoreceptor core domain. Our work exemplifies how increased OptoXR potency and new functionalities can be achieved through structure-based design towards targeted inputs into cells and cellular networks.

scholarly journals Adhesion GPCRs in Glioblastoma

2021 ◽  
Author(s):  
Gabriele Stephan ◽  
Niklas Ravn-Boess ◽  
Dimitris G Placantonakis
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
The Past ◽  
Novel Treatment ◽  
The Family ◽  
Health And Disease ◽  
Basic Biology ◽  
G Protein Coupled ◽  
Potential Use ◽  
Receptor Family

Abstract Members of the adhesion family of G protein-coupled receptors (GPCRs) have received attention for their roles in health and disease, including cancer. Over the past decade, several members of the family have been implicated in the pathogenesis of glioblastoma. Here, we discuss the basic biology of adhesion GPCRs and review in detail specific members of the receptor family with known functions in glioblastoma. Finally, we discuss the potential use of adhesion GPCRs as novel treatment targets in neuro-oncology.

scholarly journals Drug Repurposing on G Protein-Coupled Receptors Using a Computational Profiling Approach

2021 ◽  
Vol 8 ◽  
Author(s):  
Alessandra de Felice ◽  
Simone Aureli ◽  
Vittorio Limongelli
Keyword(s):  
G Protein ◽  
Drug Targets ◽  
Chemical Properties ◽  
Drug Repurposing ◽  
G Protein Coupled Receptors ◽  
Alignment Algorithm ◽  
Binding Interaction ◽  
Wide Range ◽  
G Protein Coupled ◽  
Receptor Family

G protein-coupled receptors (GPCRs) are the largest human membrane receptor family regulating a wide range of cell signaling. For this reason, GPCRs are highly desirable drug targets, with approximately 40% of prescribed medicines targeting a member of this receptor family. The structural homology of GPCRs and the broad spectrum of applications of GPCR-acting drugs suggest an investigation of the cross-activity of a drug toward different GPCR receptors with the aim of rationalizing drug side effects, designing more selective and less toxic compounds, and possibly proposing off-label therapeutic applications. Herein, we present an original in silico approach named “Computational Profiling for GPCRs” (CPG), which is able to represent, in a one-dimensional (1D) string, the physico-chemical properties of a ligand–GPCR binding interaction and, through a tailored alignment algorithm, repurpose the ligand for a different GPCR. We show three case studies where docking calculations and pharmacological data confirm the drug repurposing findings obtained through CPG on 5-hydroxytryptamine receptor 2B, beta-2 adrenergic receptor, and M2 muscarinic acetylcholine receptor. The CPG code is released as a user-friendly graphical user interface with numerous options that make CPG a powerful tool to assist the drug design of GPCR ligands.

scholarly journals Metabolite Sensing GPCRs: Promising Therapeutic Targets for Cancer Treatment?

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2345
Author(s):  
Jesús Cosín-Roger ◽  
Dolores Ortiz-Masia ◽  
Maria Dolores Barrachina ◽  
Sara Calatayud
Keyword(s):  
Cancer Treatment ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Cancer Development ◽  
Metabolic Alterations ◽  
Pharmacological Targets ◽  
G Protein Coupled ◽  
Potential Use ◽  
Shed Light ◽  
Receptor Family

G-protein-coupled receptors constitute the most diverse and largest receptor family in the human genome, with approximately 800 different members identified. Given the well-known metabolic alterations in cancer development, we will focus specifically in the 19 G-protein-coupled receptors (GPCRs), which can be selectively activated by metabolites. These metabolite sensing GPCRs control crucial processes, such as cell proliferation, differentiation, migration, and survival after their activation. In the present review, we will describe the main functions of these metabolite sensing GPCRs and shed light on the benefits of their potential use as possible pharmacological targets for cancer treatment.

Arrestin-dependent internalization of rhodopsin-like G protein-coupled receptors

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Lizzy Wanka ◽  
Victoria Behr ◽  
Annette G. Beck-Sickinger
Keyword(s):  
G Protein ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Emotional Behavior ◽  
Model Systems ◽  
Regulation Mechanism ◽  
Interaction Sites ◽  
Internalization Process ◽  
G Protein Coupled ◽  
Receptor Family

Abstract The internalization of G protein-coupled receptors (GPCRs) is an important mechanism regulating the signal strength and limiting the opportunity of receptor activation. Based on the importance of GPCRs, the detailed knowledge about the regulation of signal transduction is crucial. Here, current knowledge about the agonist-induced, arrestin-dependent internalization process of rhodopsin-like GPCRs is reviewed. Arrestins are conserved molecules that act as key players within the internalization process of many GPCRs. Based on highly conserved structural characteristics within the rhodopsin-like GPCRs, the identification of arrestin interaction sites in model systems can be compared and used for the investigation of internalization processes of other receptors. The increasing understanding of this essential regulation mechanism of receptors can be used for drug development targeting rhodopsin-like GPCRs. Here, we focus on the neuropeptide Y receptor family, as these receptors transmit various physiological processes such as food intake, energy homeostasis, and regulation of emotional behavior, and are further involved in pathophysiological processes like cancer, obesity and mood disorders. Hence, this receptor family represents an interesting target for the development of novel therapeutics requiring the understanding of the regulatory mechanisms influencing receptor mediated signaling.

scholarly journals GPR11, a Putative Seven-Transmembrane G Protein-Coupled Receptor, Controls Zoospore Development and Virulence of Phytophthora sojae

2009 ◽  
Vol 9 (2) ◽  
pp. 242-250 ◽  
Author(s):  
Yonglin Wang ◽  
Aining Li ◽  
Xiaoli Wang ◽  
Xin Zhang ◽  
Wei Zhao ◽  
...  
Keyword(s):  
G Protein ◽  
Hyphal Growth ◽  
Phytophthora Sojae ◽  
G Protein Coupled Receptors ◽  
Yeast Two Hybrid ◽  
Content Type ◽  
Signaling Mechanisms ◽  
G Protein Coupled ◽  
Two Hybrid ◽  
Receptor Family

ABSTRACT G protein-coupled receptors (GPCRs) represent a large receptor family involved in a broad spectrum of cell signaling. To understand signaling mechanisms mediated by GPCRs in Phytophthora sojae, we identified and characterized the PsGPR11 gene, which encodes a putative seven-transmembrane GPCR. An expression analysis revealed that PsGPR11 was differentially expressed during asexual development. The highest expression level occurred in zoospores and was upregulated during early infection. PsGPR11-deficienct transformants were obtained by gene silencing strategies. Silenced transformants exhibited no differences in hyphal growth or morphology, sporangium production or size, or mating behavior. However, the release of zoospores from sporangia was severely impaired in the silenced transformants, and about 50% of the sporangia did not completely release their zoospores. Zoospore encystment and germination were also impaired, and zoospores of the transformants lost their pathogenicity to soybean. In addition, no interaction was observed between PsGPR11 and PsGPA1 with a conventional yeast two-hybrid assay, and the transcriptional levels of some genes which were identified as being negatively regulated by PsGPA1 were not clearly altered in PsGPR11-silenced mutants. These results suggest that PsGPR11-mediated signaling controls P. sojae zoospore development and virulence through the pathways independent of G protein.

scholarly journals Bombesin Receptor Family Activation and CNS/Neural Tumors: Review of Evidence Supporting Possible Role for Novel Targeted Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Terry W. Moody ◽  
Lingaku Lee ◽  
Irene Ramos-Alvarez ◽  
Tatiana Iordanskaia ◽  
Samuel A. Mantey ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
G Protein ◽  
Solid Tumor ◽  
G Protein Coupled Receptors ◽  
Term Survival ◽  
Bombesin Receptor ◽  
G Protein Coupled ◽  
Receptor Family

G-protein-coupled receptors (GPCRs) are increasingly being considered as possible therapeutic targets in cancers. Activation of GPCR on tumors can have prominent growth effects, and GPCRs are frequently over-/ectopically expressed on tumors and thus can be used for targeted therapy. CNS/neural tumors are receiving increasing attention using this approach. Gliomas are the most frequent primary malignant brain/CNS tumor with glioblastoma having a 10-year survival <1%; neuroblastomas are the most common extracranial solid tumor in children with long-term survival<40%, and medulloblastomas are less common, but one subgroup has a 5-year survival <60%. Thus, there is an increased need for more effective treatments of these tumors. The Bombesin-receptor family (BnRs) is one of the GPCRs that are most frequently over/ectopically expressed by common tumors and is receiving particular attention as a possible therapeutic target in several tumors, particularly in prostate, breast, and lung cancer. We review in this paper evidence suggesting why a similar approach in some CNS/neural tumors (gliomas, neuroblastomas, medulloblastomas) should also be considered.

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