Molecular Mechanisms of Sugar Sensing by Insect Gustatory Receptors

PROJECT SUMMARY Animals desire sugars for their energy potential and for the pleasurable sensation of tasting sweetness. Despite the importance of sugar receptors in influencing nutrient sensing, metabolic responses, and taste perception, few studies have been performed to identify the molecular mechanisms underlying sugar detection and recognition. The proposed project will address this gap by integrating structural and functional studies to offer a unique perspective on the biophysical basis for sweet taste. In the first two Aims, we will focus on a single exemplary GR, Gr9 from the silk moth Bombyx mori, and couple structural methods with mutagenesis and functional assays to understand why it can only be activated by a single type of sugar, D-fructose. In Aim 1, we will investigate how this receptor binds D-fructose, how binding is coupled to the channel gate, and how different subunits within the tetramer interact cooperatively to open the ion-conducting pore. In Aim 2, we will investigate why other similarly sized sugars bind but do not activate the channel. In Aim 3, we will expand our analysis to other GRs that are activated by different sweet compounds to resolve the relationship between receptor sequence and ligand specificity. Our structural and functional analyses of GRs will provide a crucial foundation to understand how different tastants are recognized by a diverse collection of receptors and present novel routes for the design and optimization of small molecules that interfere with the gustatory systems of insect vectors of human pathogens.