G-Protein coupled receptors: structure and function in drug discovery

Odoemelam, Chiemela S.; Percival, Benita; Wallis, Helen L.; Chang, Ming Wei; Ahmad, Zeeshan; Scholey, Dawn; Burton, Emily; Williams, Ian H.; Kamerlin, Shina Caroline Lynn; Wilson, Philippe B.

doi:10.1039/d0ra08003a

Cited by 40 publications

(30 citation statements)

References 89 publications

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“…In contrast to multi-pass (integral) membrane proteins, where considerable work has been performed, in particular the GPCR class of membrane proteins e.g., [885][886][887][888][889][890][891][892][893][894][895][896][897][898][899] (for review see references: [31,[900][901][902][903]), that are a very hot topic, peripheral and bitopic (single pass) membrane proteins, which constitute 43-45% of transmembrane proteins [883], are underrepresented in MD simulation studies.…”

Section: Other Effects On Lipid Layers-pulmonary Surfactants and Indirect Effect On Membrane Proteinsmentioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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We review the use of molecular dynamics (MD) simulation as a drug design tool in the context of the role that the lipid membrane can play in drug action, i.e., the interaction between candidate drug molecules and lipid membranes. In the standard “lock and key” paradigm, only the interaction between the drug and a specific active site of a specific protein is considered; the environment in which the drug acts is, from a biophysical perspective, far more complex than this. The possible mechanisms though which a drug can be designed to tinker with physiological processes are significantly broader than merely fitting to a single active site of a single protein. In this paper, we focus on the role of the lipid membrane, arguably the most important element outside the proteins themselves, as a case study. We discuss work that has been carried out, using MD simulation, concerning the transfection of drugs through membranes that act as biological barriers in the path of the drugs, the behavior of drug molecules within membranes, how their collective behavior can affect the structure and properties of the membrane and, finally, the role lipid membranes, to which the vast majority of drug target proteins are associated, can play in mediating the interaction between drug and target protein. This review paper is the second in a two-part series covering MD simulation as a tool in pharmaceutical research; both are designed as pedagogical review papers aimed at both pharmaceutical scientists interested in exploring how the tool of MD simulation can be applied to their research and computational scientists interested in exploring the possibility of a pharmaceutical context for their research.

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Section: Other Effects On Lipid Layers-pulmonary Surfactants and Indirect Effect On Membrane Proteinsmentioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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“…In line with these results and in agreement with the anti-inflammatory and anti-oxidative actions of GTE, we found that P2Y12R-positive, neuroprotective M2, microglia significantly increases after chronic intake of GTE and translocate P2Y12R to the nucleus. The nuclear expression of this purinergic receptor in microglia following GTE supplementation is difficult to conciliate with the role of a G-protein coupled receptor such as P2Y12R, considered as a cell-surface receptor whose primary function is to transduce extracellular stimuli into intracellular signals [ 144 ]. Nevertheless, our results are in concordance with previous data on microglial activation in gliomas, in which it has been reported a shift from cytoplasmic to nuclear expression of P2Y12R linked to the acquisition of the M2 phenotype [ 90 ].…”

Section: Discussionmentioning

confidence: 99%

Beneficial effects of dietary supplementation with green tea catechins and cocoa flavanols on aging-related regressive changes in the mouse neuromuscular system

Gras

Blasco

Mòdol‐Caballero

et al. 2021

Aging

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Besides skeletal muscle wasting, sarcopenia entails morphological and molecular changes in distinct components of the neuromuscular system, including spinal cord motoneurons (MNs) and neuromuscular junctions (NMJs); moreover, noticeable microgliosis has also been observed around aged MNs. Here we examined the impact of two flavonoid-enriched diets containing either green tea extract (GTE) catechins or cocoa flavanols on age-associated regressive changes in the neuromuscular system of C57BL/6J mice. Compared to control mice, GTE- and cocoa-supplementation significantly improved the survival rate of mice, reduced the proportion of fibers with lipofuscin aggregates and central nuclei, and increased the density of satellite cells in skeletal muscles. Additionally, both supplements significantly augmented the number of innervated NMJs and their degree of maturity compared to controls. GTE, but not cocoa, prominently increased the density of VAChT and VGluT2 afferent synapses on MNs, which were lost in control aged spinal cords; conversely, cocoa, but not GTE, significantly augmented the proportion of VGluT1 afferent synapses on aged MNs. Moreover, GTE, but not cocoa, reduced aging-associated microgliosis and increased the proportion of neuroprotective microglial phenotypes. Our data indicate that certain plant flavonoids may be beneficial in the nutritional management of age-related deterioration of the neuromuscular system.

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“…From a structural perspective, all GPCRs display the same architecture—seven transmembrane alpha helices (TMs) connected by three intracellular and three extracellular loops (ICL1-3, ECL1-3). N-termini and C-termini, which the majority of GPCRs possess, can vary in length and in regulatory roles they play in GPCR signaling ( Coleman et al, 2017 ; Odoemelam et al, 2020 ).…”

Section: G Protein-coupled Receptor Related Structural Elements Of Gp...mentioning

confidence: 99%

The Many Faces of G Protein-Coupled Receptor 143, an Atypical Intracellular Receptor

Bueschbell

Manga

Schiedel

2022

Front. Mol. Biosci.

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GPCRs transform extracellular stimuli into a physiological response by activating an intracellular signaling cascade initiated via binding to G proteins. Orphan G protein-coupled receptors (GPCRs) hold the potential to pave the way for development of new, innovative therapeutic strategies. In this review we will introduce G protein-coupled receptor 143 (GPR143), an enigmatic receptor in terms of classification within the GPCR superfamily and localization. GPR143 has not been assigned to any of the GPCR families due to the lack of common structural motifs. Hence we will describe the most important motifs of classes A and B and compare them to the protein sequence of GPR143. While a precise function for the receptor has yet to be determined, the protein is expressed abundantly in pigment producing cells. Many GPR143 mutations cause X-linked Ocular Albinism Type 1 (OA1, Nettleship-Falls OA), which results in hypopigmentation of the eyes and loss of visual acuity due to disrupted visual system development and function. In pigment cells of the skin, loss of functional GPR143 results in abnormally large melanosomes (organelles in which pigment is produced). Studies have shown that the receptor is localized internally, including at the melanosomal membrane, where it may function to regulate melanosome size and/or facilitate protein trafficking to the melanosome through the endolysosomal system. Numerous additional roles have been proposed for GPR143 in determining cancer predisposition, regulation of blood pressure, development of macular degeneration and signaling in the brain, which we will briefly describe as well as potential ligands that have been identified. Furthermore, GPR143 is a promiscuous receptor that has been shown to interact with multiple other melanosomal proteins and GPCRs, which strongly suggests that this orphan receptor is likely involved in many different physiological actions.

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G-Protein coupled receptors: structure and function in drug discovery

Abstract: The G-protein coupled receptors (GPCRs) superfamily comprise similar proteins arranged into families or classes thus making it one of the largest in the mammalian genome.

Cited by 40 publications

References 89 publications

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

Beneficial effects of dietary supplementation with green tea catechins and cocoa flavanols on aging-related regressive changes in the mouse neuromuscular system

The Many Faces of G Protein-Coupled Receptor 143, an Atypical Intracellular Receptor

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