Team:HKUST/Background

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GPCRs

G protein-coupled receptors (GPCRs) are main sensors of cells. They respond to ligands such as most hormones, neurotransmitters, light, odorants, taste substances, pheromones, and varieties of medicines. GPCRs comprise one of the largest protein superfamilies: it is estimated that there are 1050 and 160 GPCR genes in the genomes of Caenorhabditis elegans and Drosophila melanogaster, corresponding to 5.5% and 1% of their total genes, respectively . To identify the ligands may lead to discovery of novel hormones, neurotransmitters ect., and should contribute to the development of new medicines. In fact, GPCRs are known to target 30-60% of present medicines.

GPCRs are seven transmembrane proteins (Fig1). Stimulated by extracellular ligands, the receptors act through heterotrimeric G proteins to regulate intracellular effector proteins. The G proteins are composed of Gα-Gβ-and Gγ-subunits. In the inactive state, the Gα-subunit is bound to GDP and associated with the Gβ-and Gγ-dimer. Upon ligand binding, the receptor stimulates the release of GDP from Gα, allowing the binding of GTP. Gα-GTP is released from the Gβ-and Gγ-dimer, and the dissociated subunits regulate the activity of effector proteins such as adenylate cyclase, phospholipase C, mitogen-activated protein kinase (MAP kinase) cascades and ion channels.

Olfactory receptors (OR) are also seven transmembrane proteins. Insect OR gene families have been identified in the fruit fly Drosophila melanogaster, the malaria vector mosquito Anopheles gambiae, the yellow fever vector mosquito Aedes aegypti, the honeybee Apis mellifera, the silkmoth Bombyx mori, and the flour beetle Tribolium castaneum. Though in vertebrates ORs consist largely of GPCRs, in insects there remains doubt whether ORs belong to GPCRs. However, various studies have been carried out on Drosophila and C. elegans G-protein coupled olfactory receptors, which has uncovered much of their structure and functions.

Based on these facts, in this iGEM project we choose to study C.elegans Odr10 GPCR to demonstrate the working principle in our design. And later we could potentially extend this study method to other insects ORs or other GPCRs.