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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 9034

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Dr. Dorota Latek

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Faculty of Chemistry, Uniwersytet Warszawski, Warsaw, Poland
Interests: computational biology; bioinformatics; cheminformatics; drug discovery; virtual screening; molecular dynamics; software development; web applications; G protein-coupled receptors; class B GPCRs
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Dear Colleagues,

G-protein-coupled receptors (GPCRs) are the largest family of plasma membrane receptors. They are involved in recognizing a diverse spectrum of ligands and mediate a broad array of cellular signaling cascades resulting into a myriad of physiological responses. Understanding the ligand recognition, activation, signaling, and regulation of these receptors is of prime importance not only to decipher aspects of human physiology but also for developing novel therapeutics. There have been remarkable developments in the broad area of GPCR biology in the past several years that have uncovered the structural mechanism of their activation, resulted in new regulatory and signaling paradigms, and allowed the use of novel methodologies to explore the functional outcomes. In this issue, all recent advances in the field of GPCR research are encouraged.

Dr. Dorota Latek
Guest Editor

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Keywords

biased signaling
activation microswitches
allosteric ligands
drug design
GPCR-targeted assays
compound profiling
orphan receptors
viral hijacking of GPCRs
cellular response
live-cell imaging

Published Papers (4 papers)

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Research

23 pages, 7622 KiB

Open AccessArticle

Keras/TensorFlow in Drug Design for Immunity Disorders

by Paulina Dragan, Kavita Joshi, Alessandro Atzei and Dorota Latek

Int. J. Mol. Sci. 2023, 24(19), 15009; https://doi.org/10.3390/ijms241915009 - 9 Oct 2023

Viewed by 1409

Abstract

Homeostasis of the host immune system is regulated by white blood cells with a variety of cell surface receptors for cytokines. Chemotactic cytokines (chemokines) activate their receptors to evoke the chemotaxis of immune cells in homeostatic migrations or inflammatory conditions towards inflamed tissue or pathogens. Dysregulation of the immune system leading to disorders such as allergies, autoimmune diseases, or cancer requires efficient, fast-acting drugs to minimize the long-term effects of chronic inflammation. Here, we performed structure-based virtual screening (SBVS) assisted by the Keras/TensorFlow neural network (NN) to find novel compound scaffolds acting on three chemokine receptors: CCR2, CCR3, and one CXC receptor, CXCR3. Keras/TensorFlow NN was used here not as a typically used binary classifier but as an efficient multi-class classifier that can discard not only inactive compounds but also low- or medium-activity compounds. Several compounds proposed by SBVS and NN were tested in 100 ns all-atom molecular dynamics simulations to confirm their binding affinity. To improve the basic binding affinity of the compounds, new chemical modifications were proposed. The modified compounds were compared with known antagonists of these three chemokine receptors. Known CXCR3 compounds were among the top predicted compounds; thus, the benefits of using Keras/TensorFlow in drug discovery have been shown in addition to structure-based approaches. Furthermore, we showed that Keras/TensorFlow NN can accurately predict the receptor subtype selectivity of compounds, for which SBVS often fails. We cross-tested chemokine receptor datasets retrieved from ChEMBL and curated datasets for cannabinoid receptors. The NN model trained on the cannabinoid receptor datasets retrieved from ChEMBL was the most accurate in the receptor subtype selectivity prediction. Among NN models trained on the chemokine receptor datasets, the CXCR3 model showed the highest accuracy in differentiating the receptor subtype for a given compound dataset. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors 2023)

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18 pages, 4098 KiB

Open AccessArticle

Structural Insights into M1 Muscarinic Acetylcholine Receptor Signaling Bias between Gαq and β-Arrestin through BRET Assays and Molecular Docking

by Dongxue Wang, Yunjin Yao, Shiqi Wang, Yifei Hou, Lanxue Zhao, Hao Wang, Hongzhuan Chen and Jianrong Xu

Int. J. Mol. Sci. 2023, 24(8), 7356; https://doi.org/10.3390/ijms24087356 - 16 Apr 2023

Cited by 1 | Viewed by 2840

Abstract

The selectivity of drugs for G protein-coupled receptor (GPCR) signaling pathways is crucial for their therapeutic efficacy. Different agonists can cause receptors to recruit effector proteins at varying levels, thus inducing different signaling responses, called signaling bias. Although several GPCR-biased drugs are currently being developed, only a limited number of biased ligands have been identified regarding their signaling bias for the M1 muscarinic acetylcholine receptor (M1mAChR), and the mechanism is not yet well understood. In this study, we utilized bioluminescence resonance energy transfer (BRET) assays to compare the efficacy of six agonists in inducing Gαq and β-arrestin2 binding to M1mAChR. Our findings reveal notable variations in agonist efficacy in the recruitment of Gαq and β-arrestin2. Pilocarpine preferentially promoted the recruitment of β-arrestin2 (∆∆RAi = −0.5), while McN-A-343 (∆∆RAi = 1.5), Xanomeline (∆∆RAi = 0.6), and Iperoxo (∆∆RAi = 0.3) exhibited a preference for the recruitment of Gαq. We also used commercial methods to verify the agonists and obtained consistent results. Molecular docking revealed that certain residues (e.g., Y404, located in TM7 of M1mAChR) could play crucial roles in Gαq signaling bias by interacting with McN-A-343, Xanomeline, and Iperoxo, whereas other residues (e.g., W378 and Y381, located in TM6) contributed to β-arrestin recruitment by interacting with Pilocarpine. The preference of activated M1mAChR for different effectors may be due to significant conformational changes induced by biased agonists. By characterizing bias towards Gαq and β-arrestin2 recruitment, our study provides insights into M1mAChR signaling bias. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors 2023)

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14 pages, 1579 KiB

Open AccessArticle

Starvation Induces Extracellular Accumulation of Polyphosphate in Dictyostelium discoideum to Inhibit Macropinocytosis, Phagocytosis, and Exocytosis

by Ramesh Rijal, Issam Ismail, Shiyu Jing and Richard H. Gomer

Int. J. Mol. Sci. 2023, 24(6), 5923; https://doi.org/10.3390/ijms24065923 - 21 Mar 2023

Cited by 1 | Viewed by 1647

Abstract

Dictyostelium discoideum is a soil-dwelling unicellular eukaryote that accumulates extracellular polyphosphate (polyP). At high cell densities, when the cells are about to overgrow their food supply and starve, the corresponding high extracellular concentrations of polyP allow the cells to preemptively anticipate starvation, inhibit proliferation, and prime themselves to begin development. In this report, we show that starved D. discoideum cells accumulate cell surface and extracellular polyP. Starvation reduces macropinocytosis, exocytosis, and phagocytosis, and we find that these effects require the G protein-coupled polyP receptor (GrlD) and two enzymes, Polyphosphate kinase 1 (Ppk1), which is required for synthesizing intracellular polyP, cell surface polyP, and some of the extracellular polyP, and Inositol hexakisphosphate kinase (I6kA), which is required for cell surface polyP and polyP binding to cells, and some of the extracellular polyP. PolyP reduces membrane fluidity, and we find that starvation reduces membrane fluidity; this effect requires GrlD and Ppk1, but not I6kA. Together, these data suggest that in starved cells, extracellular polyP decreases membrane fluidity, possibly as a protective measure. In the starved cells, sensing polyP appears to decrease energy expenditure from ingestion, and decrease exocytosis, and to both decrease energy expenditures and retain nutrients. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors 2023)

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13 pages, 2454 KiB

Open AccessArticle

GB83, an Agonist of PAR2 with a Unique Mechanism of Action Distinct from Trypsin and PAR2-AP

by Yunkyung Heo, Eunhee Yang, Yechan Lee, Yohan Seo, Kunhi Ryu, Hyejin Jeon and Wan Namkung

Int. J. Mol. Sci. 2022, 23(18), 10631; https://doi.org/10.3390/ijms231810631 - 13 Sep 2022

Cited by 1 | Viewed by 2061

Abstract

Protease-activated receptor 2 (PAR2) is a G-protein-coupled receptor (GPCR) activated by proteolytic cleavage of its N-terminal domain. Once activated, PAR2 is rapidly desensitized and internalized by phosphorylation and β-arrestin recruitment. Due to its irreversible activation mechanism, some agonists that rapidly desensitized PAR2 have been misconceived as antagonists, and this has impeded a better understanding of the pathophysiological role of PAR2. In the present study, we found that GB83, initially identified as a PAR2 antagonist, is a bona fide agonist of PAR2 that induces unique cellular signaling, distinct from trypsin and PAR2-activating peptide (AP). Activation of PAR2 by GB83 markedly elicited an increase in intracellular calcium levels and phosphorylation of MAPKs, but in a delayed and sustained manner compared to the rapid and transient signals induced by trypsin and PAR2-AP. Interestingly, unlike PAR2-AP, GB83 and trypsin induced sustained receptor endocytosis and PAR2 colocalization with β-arrestin. Moreover, the recovery of the localization and function of PAR2 was significantly delayed after stimulation by GB83, which may be the reason why GB83 is recognized as an antagonist of PAR2. Our results revealed that GB83 is a bona fide agonist of PAR2 that uniquely modulates PAR2-mediated cellular signaling and is a useful pharmacological tool for studying the pathophysiological role of PAR2. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors 2023)

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