A new era for GPCR research: structures, biology and drug discovery

Xu, H. Eric; Xiao, Rui‐Ping

doi:10.1038/aps.2012.16

Cited by 10 publications

(5 citation statements)

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“…9 GPCRs transduce extracellular stimuli into various signaling pathways that alter cell functions, and their activity can be modulated by exogenous molecules. 10 The GPCR family is divided into six classes (A−F), the largest of which is rhodopsin family A, which accounts for approximately 84% of the entire superfamily. Numerous efforts have been made to model GPCRs on available homologous templates since the crystal structures of bacteriorhodopsin 11 and bovine rhodopsin were determined.…”

Section: ■ Introductionmentioning

confidence: 99%

“…G-protein coupled receptors comprise a transmembrane protein superfamily of great pharmacological interest . GPCRs transduce extracellular stimuli into various signaling pathways that alter cell functions, and their activity can be modulated by exogenous molecules . The GPCR family is divided into six classes (A–F), the largest of which is rhodopsin family A, which accounts for approximately 84% of the entire superfamily.…”

Section: Introductionmentioning

confidence: 99%

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Impact of Template Choice on Homology Model Efficiency in Virtual Screening

Rataj

Witek

Mordalski

et al. 2014

J. Chem. Inf. Model.

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Homology modeling is a reliable method of predicting the three-dimensional structures of proteins that lack NMR or X-ray crystallographic data. It employs the assumption that a structural resemblance exists between closely related proteins. Despite the availability of many crystal structures of possible templates, only the closest ones are chosen for homology modeling purposes. To validate the aforementioned approach, we performed homology modeling of four serotonin receptors (5-HT1AR, 5-HT2AR, 5-HT6R, 5-HT7R) for virtual screening purposes, using 10 available G-Protein Coupled Receptors (GPCR) templates with diverse evolutionary distances to the targets, with various approaches to alignment construction and model building. The resulting models were further validated in two steps by means of ligand docking and enrichment calculation, using Glide software. The final quality of the models was determined in virtual screening-like experiments by the AUROC score of the resulting ROC curves. The outcome of this research showed that no correlation between sequence identity and model quality was found, leading to the conclusion that the closest phylogenetic relative is not always the best template for homology modeling.

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Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Impact of Template Choice on Homology Model Efficiency in Virtual Screening

Rataj

Witek

Mordalski

et al. 2014

J. Chem. Inf. Model.

View full text Add to dashboard Cite

show abstract

“…3,4 Having such a wide spectrum of receptors makes the GPCRs a frequent target for the development of drugs by the pharmaceutical industry, including those developed for treating eye disease. In fact, nearly 50% of all drugs on the market target GPCRs 5 and the most common of the drug classes for treating the disease of glaucoma are drugs that act through GPCRs. For POAG, most agents developed focused on regulating aqueous humor inflow and outflow.…”

mentioning

confidence: 99%

Targets of Neuroprotection in Glaucoma

Stankowska

Ellis

et al. 2018

Journal of Ocular Pharmacology and Therapeutics

101

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Progressive neurodegeneration of the optic nerve and the loss of retinal ganglion cells is a hallmark of glaucoma, the leading cause of irreversible blindness worldwide, with primary open-angle glaucoma (POAG) being the most frequent form of glaucoma in the Western world. While some genetic mutations have been identified for some glaucomas, those associated with POAG are limited and for most POAG patients, the etiology is still unclear. Unfortunately, treatment of this neurodegenerative disease and other retinal degenerative diseases is lacking. For POAG, most of the treatments focus on reducing aqueous humor formation, enhancing uveoscleral or conventional outflow, or lowering intraocular pressure through surgical means. These efforts, in some cases, do not always lead to a prevention of vision loss and therefore other strategies are needed to reduce or reverse the progressive neurodegeneration. In this review, we will highlight some of the ocular pharmacological approaches that are being tested to reduce neurodegeneration and provide some form of neuroprotection.

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“…GPCRs are integral plasma membrane proteins that transduce signals from extracellular ligands to intracellular heterotrimeric G proteins [5] . These receptors are responsible for detecting a diversity of ligands and are involved in growth, death, movement, transcription and excitation [6] .…”

Section: Sstr2 Contributes To Self-renewal Of Mescs Via Activation Ofmentioning

confidence: 99%

“…GPCRs are plasma membrane proteins that transduce sig-nals from extracellular ligands to intracellular heterotrimeric GTP-binding proteins (G proteins) [5] . GPCRs are the thirdlargest gene family in the human genome, representing over 800 distinct genes and 2% of the human genome.…”

Section: Introductionmentioning

confidence: 99%