The GPCR Network: a large-scale collaboration to determine human GPCR structure and function

Stevens, Raymond C.; Cherezov, Vadim; Katritch, Vsevolod; Abagyan, Ruben; Kühn, Peter; Rosen, Hugh; Wüthrich, Kurt

doi:10.1038/nrd3859

Cited by 268 publications

(266 citation statements)

References 64 publications

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“…Briefly, (i) whereas all GPCRs are characterized by sharing a common seventransmembrane (7TM) domain, responsible of G protein/β-arrestin activation, most class C GPCRs include, in addition, an extracellular large domain, the Venus Flytrap (VFT) and a cysteine rich domain (CRD) connecting both [30]. To date, no class C-GPCR 7TM domain has been characterized structurally, although some authors anticipate some progress in this respect, even in the short term [34]. (ii) The full or partial presence of the whole domain structure confers a high sequence-length variability to this family.…”

Section: Methodsmentioning

confidence: 99%

“…In particular, one of the most active initiatives in the field, the GPCR Network (responsible for the determination of 12 out of 21 current crystal GPCR structures) aimed at achieving 40-60% structural coverage of non-olfactory receptors for the 2010-2015 period by a combination of experimentally solved structures and computationally predicted GPCR 3D-models, if a 35% sequence identity is established as a threshold for GPCR accurate homology modeling [34].…”

Section: Methodsmentioning

confidence: 99%

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The influence of alignment-free sequence representations on the semi-supervised classification of class C G protein-coupled receptors

Cruz-Barbosa

Vellido

Giraldo

2014

Med Biol Eng Comput

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G protein-coupled receptors (GPCRs) are integral cell membrane proteins of relevance for pharmacology. The tertiary structure of the transmembrane domain, a gate to the study of protein functionality, is unknown for almost all members of class C GPCRs, which are the target of the current study. As a result, their investigation must often rely on alignments of their amino acid sequences. Sequence alignment entails the risk of missing relevant information. Various approaches have attempted to circumvent this risk through alignment-free transformations of the sequences on the basis of different amino acid physicochemical properties. In this paper, we use several of these alignment-free methods, as well as a basic amino acid composition representation, to transform the available sequences. Novel semi-supervised statistical machine learning methods are then used to discriminate the different class C GPCRs types from the transformed data. This approach is relevant due to the existence of orphan proteins to which type labels should be assigned in a process of deorphanization or reverse pharmacology. The reported experiments show that the proposed techniques provide accurate classification even in settings of extreme class-label scarcity and that fair accuracy can be achieved even with very simple transformation strategies that ignore the sequence ordering.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The influence of alignment-free sequence representations on the semi-supervised classification of class C G protein-coupled receptors

Cruz-Barbosa

Vellido

Giraldo

2014

Med Biol Eng Comput

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“…The GPCR family containing seven transmembrane domains function as the receptors for various classes of ligands, such as growth factors, chemokines and peptide hormones, and have become major targets for pharmaceutical development (Lagerström et al, 2008;Lappano et al, 2011;Stevens et al, 2013). Several GPCRs, including chemokine (C-X-C) receptors and thyroid-stimulating hormone receptor, have also been found to contribute to carcinogenesis (Xing et al, 2003;Brewer et al, 2007;Obermajer et al, 2011;Sengupta et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Lgr4 Promotes Glioma Cell Proliferation through Activation of Wnt Signaling

Yu¹,

Liang²,

Du³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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The key signaling networks regulating glioma cell proliferation remain poorly defined. The leucine-rich repeat containing G-protein coupled receptor 4 (Lgr4) has been implicated in intestinal, gastric, and epidermal cell functions. We investigated whether Lgr4 functions in glioma cells and found that Lgr4 expression was significantly increased in glioma tissues. In addition, Lgr4 overexpression promoted while its knockdown using small interfering RNA oligos inhibited glioma cell proliferation. In addition, Wnt/β-catenin signaling was activated in cells overexpressing Lgr4. Therefore, our results revealed that Lgr4 activates Wnt/β-catenin signaling to regulate glioma cell proliferation.

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“…In addition to their key role in major signaling pathways, such as sensing (e.g., smell, light, hormones or neurotransmitters), numerous drugs and toxins also act through GPCR proteins. Regulation of blood plasma calcium levels and water reabsorption in the kidney are both achieved by the functioning of specific GPCRs [8,9].…”

Section: Role Of Membrane Proteins In Health Disease and Medical Diagnmentioning

confidence: 99%

Cell Surface Membrane Proteins as Personalized Biomarkers: Where we Stand and Where we are Headed

et al. 2013

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Personalized medicine requires the development of a wide array of biomarker diagnostic assays, reflecting individual variations and thus allowing tailored therapeutic interventions. Membrane proteins comprise approximately 30% of total human proteins; they play a key role in various physiological functions and pathological conditions, although, currently, only a limited number of membrane proteins are applied as biomarkers. In many normal tissues, cell surface membrane proteins are not easily accessible for diagnostic sampling, and tumor-derived membrane preparations – while serving as potential tumor biomarkers – may not reflect physiological protein expression. In addition to post-translational modifications, which may include glycosylation, phosphorylation and lipid modifications, the trafficking of membrane proteins is also regulated. Moreover, a tight cellular quality control monitors membrane protein maturation, and continuous removal and reinsertion, involving special signaling systems, occurs in many cases. However, cell surface membrane proteins already serve as valuable prognostic and predicative biomarkers, for example, in hematological and immunological diseases, by the determination of the cluster of differentiation markers. In this review, we demonstrate the relevance of cell surface membrane biomarkers in various diseases and call attention to the potential application of red blood cell (erythrocyte) membrane proteins in this regard. Surprisingly, red blood cells express hundreds of membrane proteins, which seem to reflect a general genetic and regulatory background, and may serve as relatively stable and easily accessible personalized membrane biomarkers. Quantitative membrane protein detection in red blood cells by flow cytometry may bring a breakthrough in this regard.

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The GPCR Network: a large-scale collaboration to determine human GPCR structure and function

Cited by 268 publications

References 64 publications

The influence of alignment-free sequence representations on the semi-supervised classification of class C G protein-coupled receptors

The influence of alignment-free sequence representations on the semi-supervised classification of class C G protein-coupled receptors

Lgr4 Promotes Glioma Cell Proliferation through Activation of Wnt Signaling

Cell Surface Membrane Proteins as Personalized Biomarkers: Where we Stand and Where we are Headed

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