致电离效应
化学
受体
配体(生物化学)
变构调节
对接(动物)
果糖
甜蜜
配体门控离子通道
生物化学
糖
G蛋白偶联受体
化学受体
品味
立体化学
生物物理学
离子通道
生物
护理部
医学
NMDA受体
作者
Joana Gomes,Shivinder Singh-Bhagania,M. Angela Cenci,Carlos Chacon Cordon,Meghna Singh,Joel A. Butterwick
标识
DOI:10.1101/2023.12.18.572227
摘要
Animals crave sugars because of their energy potential and the pleasurable sensation of tasting sweetness. Yet all sugars are not metabolically equivalent, requiring mechanisms to detect and differentiate between chemically similar sweet substances. Insects use a family of ionotropic gustatory receptors to discriminate sugars, each of which is selectively activated by specific sweet molecules. To gain insight into the molecular basis of sugar selectivity, we determined structures of Gr9, a gustatory receptor from the silkworm Bombyx mori (BmGr9), in the absence and presence of its sole activating ligand, D-fructose. These structures, along with structure-guided mutagenesis and functional assays, illustrate how specificity for D-fructose is seemingly achieved by a ligand-binding pocket that precisely matches the overall shape and pattern of chemical groups in D-fructose. However, our computational docking and experimental binding assays revealed that other sugars also bind BmGr9, yet they are unable to activate the receptor. We identified the conformational change required to open the channel gate that provides an additional layer of receptor tuning in BmGr9; only D-fructose can both fit into the pocket and simultaneously engage a bridge of two conserved aromatic residues that connects the pocket to the ion conducting pore. Thus, chemical specificity does not depend solely on the selectivity of the ligand-binding pocket, but it is an emergent property arising from a combination of receptor-ligand interactions and allosteric coupling. Our results support a model whereby coarse receptor tuning is derived from the size and chemical characteristics of the pocket, whereas fine-tuning of receptor activation is achieved through the selective engagement of an allosteric pathway that regulates ion conduction.
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