Bioinformatics Analysis Of G Protein-coupled Receptors

G protein-coupled receptors (GPCRs), comprise a large family of transmembrane receptors that sense molecules outside the cell and activate inside signal transduction pathways, and ultimately, cellular responses. They are involved in many diseases, and are the target of around half of all modern medicinal drugs. However, traditional techniques to analyze GPCRs were limited. In this study, we used bioinformatics approaches to study two important problems related to G protein-coupled receptors.First, G protein-coupled receptors (GPCRs) occupied the highest hierarchic positions in the regulations of many physiological processes in insects. They had been extensively studied in a number of model eukaryotes, such as Drosophila melanogaster and Anopheles gambiae, yet not in large lepidopteran insects such as Bombyx mori, which enjoyed distinctive advantages in experiments, allowing detailed tissue expression analyses that may help to characterize insect GPCRs and their ligands. In this work, we computationally identified 90 putative GPCRs in silkworm, with 33 of them novel. Their potential functions and relationships to GPCRs in other model insects were extensively discussed.Second, one important issue in G protein-coupled receptor function analysis is the mechanism of GPCR-G protein coupling selectivity. Although several experimental and computational analyses have been attempted, the exact mechanism remains largely unknown. With the help of structural biology and computational biology, we used molecular modeling to simulate the interactions between human cannabinoid receptor CB1 and G protein. In this work, we found that the second intracellular loop (ICL2) of CB1, especially the hydrophobic amino acid leucine-222, played a critical role in G protein coupling and specificity. In addition, we proposed a dihedral angle hypothesis that was related to G protein coupling and was strongly supported by experimental evidences.