Content | |
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Description | G protein-coupled receptor data, web tools & diagrams |
Data types captured | Structures, mutants, sequences |
Contact | |
Research center | University of Copenhagen |
Authors | Vignir Isberg, Bas Vrolin, Gert Vriend, David Gloriam and others. |
Primary citation | Pandy-Szekeres G, Munk C, Tsonkov TM, Mordalski S, Harpsoe K, Hauser AS, Bojarski AJ, Gloriam DE. [1] |
Release date | 1993 |
Access | |
Website | https://www.gpcrdb.org |
Web service URL | https://gpcrdb.org/services/ |
Miscellaneous | |
Curation policy | Manual and experimental data-derived |
The GPCRdb database is the main repository of curated data for G protein-coupled receptors (GPCRs). It integrates various web tools and diagrams for GPCR analysis and stores manual annotations of all GPCR crystal structures made available through the PDB (Protein Data Bank), has the largest collections of receptor mutants and reference sequence alignments. A series of tools made available in the homepage for the GPCRdb can be run in the web browser to analyze structures, sequence similarities, receptor relationships, homology models, drug trends, genetic variants and ligand target profiles. Diagrams illustrate receptor sequences (using snake-plots and helix box diagrams) and relationships (phylogenetic trees).
According to Gert Vriend, one of the creators of the GPCRdb, the resource began in the following way:
"The GPCRdb was started in the early 90’s when Bob Bywater, Ad IJzerman, Friedrich Rippmann, and Gert Vriend organized a series of small GPCR workshops at the EMBL. Before the introduction of the first browsers, the GPCRdb worked as an automatic Email answering system that could send sequences, alignments, and homology models to the users.In 1994 the internet was firmly established in its present form, and money was obtained from the fourth EU framework to set up the GPCRdb. Florence Horn joined us to do this project. When she left us at the end of a four-year post-doc period the GPCRdb was firmly established as the prime source of information for GPCR data." [2]
Over two decades, the GPCRdb evolved to be a comprehensive information system storing and analyzing data. In 2013, the stewardship of the GPCRdb was transferred to David Gloriam's group at the University of Copenhagen, backed up by an international team of contributors and developers from a EU COST Action called ‘GLISTEN’. The GPCRdb offers reference data and easy-to-use web tools and diagrams for a multidisciplinary audience investigating GPCR function, drug design or evolution and is actively involved in the European Research Network on Signal Transduction (‘ERNEST’).
A visual overview of the main features of the GPCRdb can be glimpsed at gpcrdb.org.
The GPCRdb browsing system is structured on most relevant categories which are:
Under the categories one can find subsections for specialized data and tools.
As part of two orphan GPCR projects funded by the European Research Commission and the Lundbeck Foundation, respectively, the GPCRdb will deposit data and develop computational tools for identification of endogenous and surrogate GPCR ligands. The GPCRdb aims to grow from and enable new progress in GPCR structure, function and ligand design. It crosslinks to the GuideToPharmacology database and has adopted the official NC-IUPHAR receptor naming nomenclature, has exchange with GPCR servers, and has also recently become part of the GPCR Consortium set out to generate an unprecedented number of crystal structures. Academic and industrial groups are welcome and encouraged to contact the GPCRdb with suggestions for joint development or data deposition.
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionary related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. Coupling with G proteins, they are called seven-transmembrane receptors because they pass through the cell membrane seven times. Ligands can bind either to extracellular N-terminus and loops or to the binding site within transmembrane helices. They are all activated by agonists although a spontaneous auto-activation of an empty receptor can also be observed.
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular response. Proteins responsible for detecting stimuli are generally termed receptors, although in some cases the term sensor is used. The changes elicited by ligand binding in a receptor give rise to a biochemical cascade, which is a chain of biochemical events known as a signaling pathway.
In biochemistry, allosteric regulation is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site.
Structural bioinformatics is the branch of bioinformatics that is related to the analysis and prediction of the three-dimensional structure of biological macromolecules such as proteins, RNA, and DNA. It deals with generalizations about macromolecular 3D structures such as comparisons of overall folds and local motifs, principles of molecular folding, evolution, and binding interactions, and structure/function relationships, working both from experimentally solved structures and from computational models. The term structural has the same meaning as in structural biology, and structural bioinformatics can be seen as a part of computational structural biology. Structural bioinformatics main objectives are the creation of new methods to deal with biological macromolecules data to solve problems in biology and generate new knowledge.
In biochemistry and pharmacology, receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems. These signals are typically chemical messengers which bind to a receptor and cause some form of cellular/tissue response, e.g. a change in the electrical activity of a cell. There are three main ways the action of the receptor can be classified: relay of signal, amplification, or integration. Relaying sends the signal onward, amplification increases the effect of a single ligand, and integration allows the signal to be incorporated into another biochemical pathway.
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In protein-ligand binding, the ligand is usually a molecule which produces a signal by binding to a site on a target protein. The binding typically results in a change of conformational isomerism (conformation) of the target protein. In DNA-ligand binding studies, the ligand can be a small molecule, ion, or protein which binds to the DNA double helix. The relationship between ligand and binding partner is a function of charge, hydrophobicity, and molecular structure. The instance of binding occurs over an infinitesimal range of time and space, so the rate constant is usually a very small number.
In biochemistry, an orphan receptor is a protein that has a similar structure to other identified receptors but whose endogenous ligand has not yet been identified. If a ligand for an orphan receptor is later discovered, the receptor is referred to as an "adopted orphan". Conversely, the term orphan ligand refers to a biological ligand whose cognate receptor has not yet been identified.
In the field of molecular modeling, docking is a method which predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex. Knowledge of the preferred orientation in turn may be used to predict the strength of association or binding affinity between two molecules using, for example, scoring functions.
A receptor activated solely by a synthetic ligand (RASSL) or designer receptor exclusively activated by designer drugs (DREADD), is a class of chemogenetically-engineered proteins that permit spatial and temporal control of G protein signaling in vivo. Originally differentiated by the approach used to engineer them, RASSLs and DREADDs are often used interchangeably now to represent an engineered G-protein receptor-ligand system. These systems utilize G protein-coupled receptors (GPCR) engineered to respond exclusively to synthetic ligands, like clozapine N-oxide (CNO), and not to their natural ligand(s).
G protein-coupled receptor kinases are a family of protein kinases within the AGC group of kinases. Like all AGC kinases, GRKs use ATP to add phosphate to Serine and Threonine residues in specific locations of target proteins. In particular, GRKs phosphorylate intracellular domains of G protein-coupled receptors (GPCRs). GRKs function in tandem with arrestin proteins to regulate the sensitivity of GPCRs for stimulating downstream heterotrimeric G protein and G protein-independent signaling pathways.
P2Y receptors are a family of purinergic G protein-coupled receptors, stimulated by nucleotides such as ATP, ADP, UTP, UDP and UDP-glucose. To date, 8 P2Y receptors have been cloned in humans: P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13 and P2Y14.
UTOPIA is a suite of free tools for visualising and analysing bioinformatics data. Based on an ontology-driven data model, it contains applications for viewing and aligning protein sequences, rendering complex molecular structures in 3D, and for finding and using resources such as web services and data objects. There are two major components, the protein analysis suite and UTOPIA documents.
Latrophilin 1 is a protein that in humans is encoded by the ADGRL1 gene. It is a member of the adhesion-GPCR family of receptors. Family members are characterized by an extended extracellular region with a variable number of protein domains coupled to a TM7 domain via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
Probable G-protein coupled receptor 123 is a protein that in humans is encoded by the GPR123 gene. It is a member of the adhesion-GPCR family of receptors. Family members are normally characterized by an extended extracellular region with a variable number of protein domains coupled to a TM7 domain via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
Relaxin/insulin-like family peptide receptor 4, also known as RXFP4, is a human G-protein coupled receptor.
Secretin family receptor proteins, also known as Family B or family 2 of G-protein coupled receptors are regulated by peptide hormones from the glucagon hormone family. The family is different from adhesion G protein-coupled receptors.
Cell surface receptors are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving extracellular molecules. They are specialized integral membrane proteins that allow communication between the cell and the extracellular space. The extracellular molecules may be hormones, neurotransmitters, cytokines, growth factors, cell adhesion molecules, or nutrients; they react with the receptor to induce changes in the metabolism and activity of a cell. In the process of signal transduction, ligand binding affects a cascading chemical change through the cell membrane.
A GPCR oligomer is a protein complex that consists of a small number of G protein-coupled receptors (GPCRs). It is held together by covalent bonds or by intermolecular forces. The subunits within this complex are called protomers, while unconnected receptors are called monomers. Receptor homomers consist of identical protomers, while heteromers consist of different protomers.
The IUPHAR/BPS Guide to PHARMACOLOGY is an open-access website, acting as a portal to information on the biological targets of licensed drugs and other small molecules. The Guide to PHARMACOLOGY is developed as a joint venture between the International Union of Basic and Clinical Pharmacology (IUPHAR) and the British Pharmacological Society (BPS). This replaces and expands upon the original 2009 IUPHAR Database. The Guide to PHARMACOLOGY aims to provide a concise overview of all pharmacological targets, accessible to all members of the scientific and clinical communities and the interested public, with links to details on a selected set of targets. The information featured includes pharmacological data, target and gene nomenclature, as well as curated chemical information for ligands. Overviews and commentaries on each target family are included, with links to key references.
Marta Filizola is a computational biophysicist who studies membrane proteins. Filizola's research concerns drug discovery the application of methods of computational chemistry and theoretical chemistry to biochemical and biomedical problems.