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PubMed2002

Annotating the human proteome: the Human Proteome Survey Database (HumanPSD) and an in-depth target database for G protein-coupled receptors (GPCR-PD) from Incyte Genomics.

The Proteome Division of Incyte Genomics has released new volumes to the BioKnowledge Library to add human, mouse and rat protein information to its rich collection of model organism Proteome Databases. The Human Proteome Survey Database (HumanPSD) compiles the fundamental properties of more than 25 000 characterized mammalian proteins. HumanPSD includes clear, concise and current protein descriptions (Title Lines), the protein sequence, calculated physical properties, precomputed BLAST alignments, controlled-vocabulary protein properties and Gene Ontology terms, and a list of published references. Each report also contains expression data, Pfam domain information and an associated Mouse Mutant Phenotype section describing behavioral, physiological and cellular phenotypes for over 1500 mouse mutant phenotypes. GPCR-PD contains more than 3200 Protein Reports from the three mammalian species for G protein-coupled receptors, their protein ligands, associated G-proteins and their downstream signaling proteins. In addition to the features described above, each GPCR-PD Protein Report displays annotations of experimental findings from over 10 000 publications. These databases provide important new volumes of Proteome's BioKnowledge Library (http://www.incyte.com), integrating protein information from model organisms with the human proteome.

Amino Acid Sequence↗
PubMed2006

Statistical analysis and prediction of functional residues effective for GPCR-G-protein coupling selectivity.

One of the important issues in G-protein-coupled receptor (GPCR) functional analysis is the mechanism of GPCR-G-protein coupling selectivity. G-proteins are classified into Gi/o, Gq/11 and Gs families. Although several experimental and computational analyses have been attempted, the mechanism remains unknown to this day. In this study, we have analyzed the multiple sequence alignments of GPCRs of known coupling selectivities by mapping onto the tertiary structure of rhodopsin. We identified several functional residue sites in GPCRs related to coupling selectivity, which are located mainly at the intracellular loops, and found that the occurrence of positively/negatively charged amino acids of the characteristic residues varies depending on the G-protein coupling selectivity. Especially, the occurrence of positively charged amino acids in receptors coupling to Gs family is less than that in receptors coupling to Gi/o and Gq/11 families. It is interesting that some characteristic residues are located near the extracellular terminus of transmembrane helices, which is far from the GPCR/G-protein binding interface. In most of the receptors coupling to Gs family, the occurrence of proline on the position corresponding to the 170th residue on rhodopsin is rare. These findings are vital to improving our understanding of the mechanism of G-protein coupling selectivity.

Amino Acid Sequence↗
PubMed2003

Phosphorylation of G protein-coupled receptors: GPCR kinases in heart disease.

In the heart, beta -adrenergic receptors (beta ARs), members of the superfamily of G protein-coupled receptors (GPCRs), modulate cardiac responses to catecholamines. beta AR signaling, which is compromised in many cardiac diseases (e.g., congestive heart failure), is regulated by GPCR kinases (GRKs). Levels of the most abundant cardiac GRK, known as GRK2 or beta AR kinase 1 (beta ARK1), are increased in both animal and human heart failure. Transgenic mouse models have demonstrated that beta ARK1 plays a vital role in cardiac function and development, as well as in the regulation of myocardial signaling, and pharmacological studies have further implicated GRKs in the impairment of cardiac GPCR signaling. Gene therapy, along with the development of small-molecule modulators of GRK activity, has indicated in multiple animal models that the manipulation of GRK activity may elicit therapeutic benefits in many forms of cardiac disease.

Animals↗
PubMed2002

LSSIG is a novel murine leukocyte-specific GPCR that is induced by the activation of STAT3.

G-protein-coupled receptors (GPCRs) transduce the signal of a wide variety of chemokines, cytokines, neurotransmitters, hormones, odorants, and others to regulate the biologic homeostasis, including hematopoiesis and immunity. Here we report the molecular cloning of leukocyte-specific STAT-induced GPCR (LSSIG), which is a novel murine orphan GPCR with the highest homology to human GPR43. The mRNA expression of LSSIG was clearly induced in M1 leukemia cells during the leukemia inhibitory factor (LIF)-induced differentiation to macrophages, and the induction was evidently signal transducers and activators of transcription 3 (STAT3)-dependent. GPR43 expression was also strongly induced in HL-60 and U937 leukemia cells during the differentiation to monocytes. Further analysis showed that the expression of both LSSIG and GPR43 is highly restricted in hematopoietic tissues. Cytokine-stimulation induced LSSIG and GPR43 in bone marrow cells, and monocytes and neutrophils, respectively. These results suggest that LSSIG and GPR43 might play pivotal roles in differentiation and immune response of monocytes and granulocytes.

Animals↗
PubMed2004

Lower rate of genomic variation identified in the trans-membrane domain of monoamine sub-class of Human G-Protein Coupled Receptors: the Human GPCR-DB Database.

BACKGROUND: We have surveyed, compiled and annotated nucleotide variations in 338 human 7-transmembrane receptors (G-protein coupled receptors). In a sample of 32 chromosomes from a Nordic population, we attempted to determine the allele frequencies of 80 non-synonymous SNPs, and found 20 novel polymorphic markers. GPCR receptors of physiological and clinical importance were prioritized for statistical analysis. Natural variation and rare mutation information were merged and presented online in the Human GPCR-DB database http://cyrix.cgb.ki.se. RESULTS: The average number of SNPs per 1000 bases of exonic sequence was found to be twice the average number of SNPs per Kilobase of intronic regions (2.2 versus 1.0). Of the 338 genes, 111 were single exon genes, that is, were intronless. The average number of exonic-SNPs per single-exon gene was 3.5 (n = 395) while that for multi-exon genes was 0.8 (n = 1176). The average number of variations within the different protein domain (N-terminus, internal- and external-loops, trans-membrane region, C-terminus) indicates a lower rate of variation in the trans-membrane region of Monoamine GPCRs, as compared to Chemokine- and Peptide-receptor sub-classes of GPCRs. CONCLUSIONS: Single-exon GPCRs on average have approximately three times the number of SNPs as compared to GPCRs with introns. Among various functional classes of GPCRs, Monoamine GPRCs have lower number of natural variations within the trans-membrane domain indicating evolutionary selection against non-synonymous changes within the membrane-localizing domain of this sub-class of GPCRs.

Alleles↗
PubMed2006

G proteins in drug screening: from analysis of receptor-G protein specificity to manipulation of GPCR-mediated signalling pathways.

Seven transmembrane G protein coupled receptors (7TM GPCRs) represent one of the largest gene familes in the human genome. Because of the size of the GPCR family, their proven history of being valuable targets for small molecule drug design, the fact that the absolute number of GPCRs that are targets for current medicines represents only a small fraction of the total encoded by the human genome, and that ligands for GPCRs do not have to enter the cell to exert their function, it is very likely that GPCRs will remain major targets for the pharmaceutical industry in the foreseeable future. Despite recent evidence indicating that GPCRs can provide information to cells, that does not require activation of G proteins ("signaling at zero G"), most of the GPCRs known to date function via interaction with and activation of heterotrimeric (alphabetagamma) G proteins. Thus, assay systems translating ligand modulation of GPCRs into G protein-dependent intracellular responses are a key component of both basic research and the drug discovery process. This article will review the current knowledge and recent progress in understanding molecular aspects of specific receptor-G protein recognition. It will also highlight how the knowledge generated by such studies can be transformed into assay systems for GPCR drug discovery.

Animals↗
PubMed2004

Central G-Protein Coupled Receptors (GPCR)s as molecular targets for the treatment of obesity: assets, liabilities and development status.

In the last decade, the G-Protein-Coupled Receptor (GPCR) superfamily has emerged as a very promising and enriched source of therapeutic targets for the treatment of obesity. GPCRs represent the largest family of mammalian proteins, with approximately 1000 members. It is estimated that the GPCR family may comprise greater than 1% of the human genome and is the molecular target for approximately 30% of currently marketed drugs. Human GPCRs are modulated by a large variety of ligands, including peptides, lipids, neurotransmitters, nucleotides, ions and external sensory signals such as pheromones, tastes or odors. Many of the above ligands have been implicated in the physiological control of energy balance. This article will examine the biological rationale, assets, identified liabilities and current drug development status of these receptors as anti-obesity drug targets.

Anti-Obesity Agents↗
PubMed2002

[30 years: Happy birthday, GPCR. The bradykinin B2 receptor: an alternative and antiproliferative pathway].

The bradykinin B2 receptor which belongs to the G-protein-coupled receptor (GPCR) family is known for its proliferative effects. The mitogenic signalling pathways used are "classical" pathways for GPCRs. Recent data from our laboratory show that bradykinin can also induce anti-mitogenic effects in proliferating cells using an "alternative" signal transduction pathway involving a protein tyrosine phosphatase. Besides this alternative signalling pathway for the B2 receptor, a novel concept of GPCR signalling is described.

Animals↗
PubMed2004

Strategies for designing GPCR-focused libraries and screening sets.

In recent years drug discovery has progressively moved away from a traditional single-target focus toward a family-based approach. The development of knowledge relating to targets and ligands of the same protein family has been actively pursued to support more predictive and efficient pharmaceutical research. The design of focused libraries and screening sets for the G protein-coupled receptor (GPCR) family has been undertaken along several different routes. A first approach has been ligand-based, relying either on physicochemical properties or on privileged substructures of GPCR ligands, but despite some success this approach has suffered from the near absence of knowledge coming from the receptor. To strengthen the weak link between the chemical and biological aspects, new databases have been developed and have steadily moved toward integrated information systems. Several research groups have reported novel approaches to library design and compound selection based on two- or three-dimensional mapping of the ligand-receptor interaction sites. The development of homology models derived from the rhodopsin crystal structure, the use of site-directed mutagenesis in relation to ligand structure-activity relationships (SARs), and the integration of informatics analyses have been critical elements for driving new designs in a modern chemogenomics environment.

Binding Sites↗
PubMed2004

GPCR allosterism and accessory proteins: new insights into drug discovery, 17 July 2004, Glasgow, Scotland.

This satellite meeting provided an insight into the current status and progress with GPCR allosterism and interacting accessory proteins. With one compound on the market (cinacalcet) and several others in clinical development (eg, targeting M1 and mGluR2), it is clear that targeting allosteric sites on GPCRs represents a valid approach to identifying novel drugs. Targeting allosteric sites may confer additional selectivity and permit conformational changes in GPCRs to enable disruption of large protein-protein interactions (eg, CCR5). Despite emerging research on the potential of interacting accessory proteins as drug targets, further research to understand these interactions are required before initiating focused drug discovery programs that specifically target GPCR-interacting proteins.

Allosteric Regulation↗
PubMed2025

Spatiotemporally resolved GPCR interactome uncovers unique mediators of receptor agonism.

Cellular signaling by membrane G protein-coupled receptors (GPCRs) is governed by a complex and diverse array of mechanisms. The dynamics of a GPCR interactome, as it evolves over time and space in response to an agonist, provide a unique perspective on pleiotropic signaling decoding and functional selectivity at the cellular level. In this study, we utilized proximity-based APEX2 proteomics to investigate the interaction network of the luteinizing hormone receptor (LHR) on a minute-to-minute timescale. We developed an analytical approach that integrates quantitative multiplexed proteomics with temporal reference profiles, creating a platform to identify the proteomic environment of APEX2-tagged LHR at the nanometer scale. LHR activity is finely regulated spatially, leading to the identification of putative interactors, including the Ras-related GTPase RAP2B, which modulate both receptor signaling and post-endocytic trafficking. This work provides a valuable resource for spatiotemporal nanodomain mapping of LHR interactors across subcellular compartments.

Humans↗
PubMed2005

Characterization of novel GPCR gene coding locus in amphioxus genome: gene structure, expression, and phylogenetic analysis with implications for its involvement in chemoreception.

Chemosensation is the primary sensory modality in almost all metazoans. The vertebrate olfactory receptor genes exist as tandem clusters in the genome, so that identifying their evolutionary origin would be useful for understanding the expansion of the sensory world in relation to a large-scale genomic duplication event in a lineage leading to the vertebrates. In this study, I characterized a novel GPCR (G-protein-coupled receptor) gene-coding locus from the amphioxus genome. The genomic DNA contains an intronless ORF whose deduced amino acid sequence encodes a seven-transmembrane protein with some amino acid residues characteristic of vertebrate olfactory receptors (ORs). Surveying counterparts in the Ciona intestinalis (Asidiacea, Urochordata) genome by querying BLAST programs against the Ciona genomic DNA sequence database resulted in the identification of a remotely related gene. In situ hybridization analysis labeled primary sensory neurons in the rostral epithelium of amphioxus adults. Based on these findings, together with comparison of the developmental gene expression between amphioxus and vertebrates, I postulate that chemoreceptive primary sensory neurons in the rostrum are an ancient cell population traceable at least as far back in phylogeny as the common ancestor of amphioxus and vertebrates.

Amino Acid Sequence↗
PubMed1996

Molecular cloning of the novel human G protein-coupled receptor (GPCR) gene mapped on chromosome 9.

A novel human GPCR gene was cloned by PCR with degenerate primers designed from cannabinoid type 1 receptor (CB1) sequences and a full-length clone was isolated by screening of a human genomic DNA library. This gene, termed EDG-3, is highly homologous (51.9 % overall and 69.2 % in seven transmembrane regions) to human EDG-1, 47.9 % to rat AGR16 but only 28.0 % to human CB1 receptor. The Northern hybridization analysis showed that a 2.8 kb transcript of EDG-3 is abundantly expressed in the heart followed by placenta, kidney and liver. The EDG-3 gene was mapped on the human chromosome 9q22.1-q22.2 by fluorescence in situ hybridization analysis. Although the ligand and physiological role of this receptor is unknown, this gene may be a new member of the EDG family.

Amino Acid Sequence↗
PubMed2006

Direct analysis of a GPCR-agonist interaction by surface plasmon resonance.

Despite their clinical importance, detailed analysis of ligand binding at G-protein coupled receptors (GPCRs) has proved difficult. Here we successfully measure the binding of a GPCR, neurotensin receptor-1 (NTS-1), to its ligand, neurotensin (NT), using surface plasmon resonance (SPR). Specific responses were observed between NT and purified, detergent-solublised, recombinant NTS-1, using a novel configuration where the biotinylated NT ligand was immobilised on the biosensor surface. This SPR approach shows promise as a generic approach for the study of ligand interactions with other suitable GPCRs.

Animals↗
PubMed2006

Balancing focused combinatorial libraries based on multiple GPCR ligands.

G-Protein coupled receptors (GPCRs) are important targets for drug discovery, and combinatorial chemistry is an important tool for pharmaceutical development. The absence of detailed structural information, however, limits the kinds of combinatorial design techniques that can be applied to GPCR targets. This is particularly problematic given the current emphasis on focused combinatorial libraries. By linking an incremental construction method (OptDesign) to the very fast shape-matching capability of ChemSpace, we have created an efficient method for designing targeted sublibraries that are topomerically similar to known actives. Multi-objective scoring allows consideration of multiple queries (actives) simultaneously. This can lead to a distribution of products skewed towards one particular query structure, however, particularly when the ligands of interest are quite dissimilar to one another. A novel pivoting technique is described which makes it possible to generate promising designs even under those circumstances. The approach is illustrated by application to some serotonergic agonists and chemokine antagonists.

Combinatorial Chemistry Techniques↗
PubMed2006

Lipid-protein interactions in GPCR-associated signaling.

Signal transduction via G-protein-coupled receptors (GPCRs) is a fundamental pathway through which the functions of an individual cell can be integrated within the demands of a multicellular organism. Since this family of receptors first discovered, the proteins that constitute this signaling cascade and their interactions with one another have been studied intensely. In parallel, the pivotal role of lipids in the correct and efficient propagation of extracellular signals has attracted ever increasing attention. This is not surprising given that most of the signal transduction machinery is membrane-associated and therefore lipid-related. Hence, lipid-protein interactions exert a considerable influence on the activity of these proteins. This review focuses on the post-translational lipid modifications of GPCRs and G proteins (palmitoylation, myristoylation, and isoprenylation) and their significance for membrane binding, trafficking and signaling. Moreover, we address how the particular biophysical properties of different membrane structures may regulate the localization of these proteins and the potential functional consequences of this phenomenon in signal transduction. Finally, the interactions that occur between membrane lipids and GPCR effector enzymes such as PLC and PKC are also considered.

Cell Membrane↗
PubMed2006

CD312, the human adhesion-GPCR EMR2, is differentially expressed during differentiation, maturation, and activation of myeloid cells.

EMR2/CD312 is a member of the adhesion-GPCR family that contains extracellular EGF-like domains. Previously it has been shown to interact with chondroitin sulphate glycosaminoglycans in an isoform-specific manner. Although EMR2 expression has been found to be restricted to human myeloid cells, its expression profile has not yet been systemically characterized. In this report, we show that EMR2 receptor expression is up-regulated during differentiation and maturation of macrophages, and is conversely down-regulated during dendritic cell maturation. We also demonstrate that EMR2 receptor alternative splicing and glycosylation is regulated during myeloid differentiation. In monocytes and macrophages, EMR2 can be specifically up-regulated by LPS and IL-10 via an IL-10-mediated pathway. In inflamed tissues, EMR2 is detected in subpopulations of myeloid cells including macrophages and neutrophils. The results presented here further support the idea that EMR2 plays a role in the migration and adhesion of myeloid cells during cell differentiation, maturation, and activation.

Cell Differentiation↗
PubMed2005

Fluorophore-tagged GPCR ligands.

Fluorescently tagged drug molecules can be successfully employed to visualize the location of their receptor target at the single-cell level. Furthermore, if their binding to the receptor is reversible, one can now obtain detailed pharmacological information such as affinity using single-molecule detection techniques. When coupled to the growing exploitation of fluorescence-based read-outs in high throughput and high content screening, it is clear that fluorescent molecules offer a safer, more powerful and more versatile alternative to radioligands in molecular pharmacology and drug discovery. GPCR pharmacology has benefited enormously from the application of fluorescence-based technologies and we now possess a much greater understanding of this receptor family's basic molecular mechanisms of action through the careful design and judicious use of fluorescent peptide and small-molecule-based ligands.

Fluorescent Dyes↗