Vol.3 No.1 2010

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Research paper : A bioinformatics strategy to produce a cyclically developing project structure (M. Suwa et al.)−2−Synthesiology - English edition Vol.3 No.1 (2010) the GPCR is expressed and can function upon bonding with the G protein. However, since the type of coupled G protein is unknown to the GPCR, it is necessary to set up the experimental systems for all the cell environments where the GPCR is combined with several major types of G proteins. Even if one is capable of reaching this phase, it is difficult to achieve further high efficiency. In the following chapters, we shall present an approach from the standpoint of bioinformatics to reduce the above-mentioned risks as much as possible, using the GPCR research (hereinafter, referred to as “the Project”) that we have been doing as a model case. 2 Objective of research and research scenario to achieve the objectivesThe initial objective of the Project that was started in 2000 was “to present information that contributes to the experimental design by predicting the experimental result with bioinformatics technology, to minimize the risk of biochemical experiment for GPCR drug discovery.” Specific objectives were: (1) to comprehensively identify and retain the human GPCR genes including the new genes from the genome sequence and to create a database (DB), and to add functional and structural information to these genes in highly efficient manner using the computational method. If the foundation were laid for this DB, it would become easy to find the new GPCRs that may be difficult to isolate or to be expressed by the biochemical experiment. The other objective was: (2) to develop a program to predict the activation of G protein by entering the ligand and GPCR sequence information and to apply this to orphan receptors whose bonding ligands are unknown. By doing so, the combination of the GPCR and the regulatory drug could be investigated comprehensively, and the design of ligand screening experiment for the orphan receptor would be possible. This would then accelerate the pharmaceutical researches. Above two were the main objectives considered at the start of the Project. The research cycle of bioinformatics, which ranges from basic research to application, is short and as such, the results will instantly become “products” in the form of DB and programs. As the cycle of a typical Full Researchcould be completed in a visible manner, we thought this would be a milestone. In fact, this would not be the end of the cycle, but it was impossible to correctly draft any future research scenario since the advancement of the life science field was extremely fast. However, we did have some expectations that we would be dealing with a larger flow based on our “product.” Right from the beginning, we could predict that the Project would take several years to be accomplished. 3 First cycle of Full ResearchFollowing is a description of the first cycle of the research since the Project was started. It started from identifying the genes from the human genome sequence.3.1 Gene identification from the genome sequenceThe genome is the blueprint of life written on the chromosomes in the cell nucleus. Identifying genes using the computer is like finding a region that has the characteristics of the gene from the DNA (deoxyribonucleic acid) sequence recorded as a long text file. [According to recent understanding, “gene region” has a wide meaning, as it includes the region that codes the functional RNA (ribonucleic acid) as well as the region that codes protein. In this paper, for the sake of discussion, we limit the “gene region” to mean the code region of protein only.] In most eukaryotes, the genes are separated by several regions called the intron on the genome DNA sequence (Fig. 2). Before this information finally becomes the protein, it is transcribed to mRNA, the introns are cut off, mature mRNA that is bonded only to the exon region of the separated side is formed, and this is then translated into an amino acid sequence. The sequence of three sets of bases that correspond to one code of amino acid during translation is called the codon. When the DNA sequence is read in order in units of codon, there will be a codon sequence for the starting point. There can be six different codon sequences, including those where one or two bases are shifted from the starting point Fig. 1 Conceptual diagram for G protein coupled receptors (GPCR).The GPCRs are present in the cell membrane at places such as the neural junction (right). Various types of molecules (ligands) from extracellular area bond to the structure that is composed by seven transmembrane helices, whereby activating the coupled G proteins, and the signaling pathway to the cell are determined by the G protein type (roughly 3 types) (left). GαβγCell membrane surfaceSignal transductionNeural junction, terminals of gustatory and olfactory nerves etc.Extracellular areaCytoplasmic areaLigandCoupled G proteinGPCRTransduction system that inhibits the releaseof adenylate cyclaseTransduction system that activates the releaseof adenylate cyclaseTransduction system that activates phospholipase C

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