Retrieval of Receptor Information and Signal Transduction Pathways

The receptors are classified according to membrane receptors and nuclear receptors, which are also listed alphabetically for retrieval at Receptor database (http:// impact.nihs.go.jp/RDB.html) (Nakata et al., 1999). A keyword query can be

Figure 6.1. DynaFit start windows. After loading script file, the program automatically inputs data file and plots raw data in the graphic window. Start the analysis (File^Run!) upon receiving "Ready to run'' instruction in the status window.
Figure 6.2. DynaFit result windows. After answering Yes to questions, "Is the initial estimate good enough?'' and "Terminate the least-squares minimization?'', the program terminates by plotting fitted results in the Graphic window and summary in the Text window.

Figure 6.3. G Protein-coupled receptor retrieved from GPCRDB.Seven transmembrane segment receptor for serotonin retrieved from GPCRDB is visualized in a snake-like plot. The colored groups of residues show a correlated behavior as determined by correlated mutation analysis (CMA). The colored positions are hyperlinked to their corresponding residue locations in the multiple sequence alignments.

Figure 6.3. G Protein-coupled receptor retrieved from GPCRDB.Seven transmembrane segment receptor for serotonin retrieved from GPCRDB is visualized in a snake-like plot. The colored groups of residues show a correlated behavior as determined by correlated mutation analysis (CMA). The colored positions are hyperlinked to their corresponding residue locations in the multiple sequence alignments.

initiated to search for a specific receptor, its link to sequence databases (Gen-Bank,PIR, and SWISS-PROT), and multiple alignment of a receptor family via MView option. GPCRDB at http://www.gpcr.org/7tm/ and NucleaRDB at http:// www.receptors.org/NR/ or http://www.gpcr.org/NR/ are Information Systems for G protein-coupled receptors (Figure 6.3) and nuclear receptors, respectively (Horn et al., 2001). Both sites provide links to sequence databases, bibliographic references, alignments, and phylogenetic trees based on sequence data. In addition, GPCRDB also provides mutation data, lists of available pdb files, and tables of ligand binding constants to receptors of acetylcholine, adrenaline, dopamine, histamine, serotonin, opioid, adenosine, cannabis, melatonin, and y-aminobutyric acid.

The information for signaling pathways in human cells can be retrieved from the Cell Signaling Network Database (CSNDB) (Takai-Igarashi et al., 1998) at http:// geo.nihs.go.jp/csndb/ (Figure 6.4). Under Global Search, enter the ligand name (e.g., ACTH, estradiol) as the keyword and click Send Request. The search returns list of information (signaling cell, function, and structure link). Click Find Pathways to view the sketch of signal pathway with clickable links. Alternatively, you may click Browse and select EndoMolecules (e.g., hormones) or ExoMolecules (e.g., drugs) to view signal pathways.

Figure 6.4. Cell signaling networks database. The cell signaling networks database (CSNDB) provides facilities for searching/retrieving transduction (signaling) pathways.

The Biomolecular Interaction Network Database (BIND) at http://www. binddb.org/ (Bader et al., 2001) provides a text query for information on biomolecular interactions relating to cellular communication, differentiation, and growth. Enter the name of receptor or second messenger but not ligand (e.g., the text query accepts dopamine receptor but not dopamine) and click Find. This returns a list of hits. Select the Interaction ID (full record) or desired information (Full record, PubMed abstract, BIND publication, View ASN report, or View XML report). Click Visualize Interaction to open the Interaction Viewer window showing the interaction between two components in the signaling pathway (Figure 6.5). Further interactions involving the pathway members can be viewed by double-clicking the highlighted boxes.

ReliBase at http://relibae.ebi.aci.uk/ is the resource site for receptor - ligand (Reli) interactions and provides facilities for similarity search/analysis of the Reli database for similar ligands, similar binding sites, and Reli complex (Figure 6.6). The query at ReliBase can be conducted via Text (e.g., chemical name of ligand), Sequence (of receptor), Smiles (strings), or 2D/3D (fragments of structure) of ligand by clicking respective menu button. The instructions on how to use Relibase can be obtained by clicking the Help button. A ligand and its receptor complex can be searched/retrieved by entering the ligand name after clicking Text button or entering SMILES string (by clicking the Smiles button). To save the atomic coordinate file (pdb format) of a ligand-binding complex, click Complex PDB file. To search for similar ligands with a receptor sequence, click Sequence on the ReliBase home page.

Figure 6.5. BIND Information and interaction viewer. The full record of BIND is shown for an interaction involving Ras. Clicking Visualize Interaction opens the Interaction viewer window. Activate (double-click) the highlighted molecule displays further interactions.
Figure 6.6. Relibase home page. Relibase provides resources for searching/retrieving structures, binding sites of receptor proteins, and chemical diagram of ligands. All nonprotein moieties (except water) in the PDB complexes are considered as ligands.

Copy and paste the amino acid sequence into the query box and click Show Ligands. Clicking the 2D/3D button opens the structure window for drawing a structure component used to search the database by substructure.

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