Mechanism of Agonism-Antagonism of Sweet Taste Receptors

描述（由申请人提供）：本申请的目标是开发人甜味受体的跨膜（TM）结构域内的激动剂和拮抗剂结合位点的分子模型。我们选择了甜味剂甜蜜素和拮抗剂乳糖醇作为研究对象。我们将通过分子对接确定甜味剂和甜味抑制剂的甜味受体中的结合口袋，这些结合口袋已知在TM结构域中结合，并将通过诱变研究进行测试。模型受体和对接的复合物将作为分子动力学模拟的初始结构，试图了解甜味反应的激活和抑制的潜在机制。甜味受体的激动剂和拮抗剂结合和激活/抑制的分子机制可能导致基于结构的新型无热量甜味剂的合理设计，这将有助于对抗肥胖和糖尿病。了解味觉反应机制对于为味觉障碍患者开发新的治疗方法也很重要。

DESCRIPTION (provided by applicant): The goal of the current application is to develop molecular models of agonist and antagonist binding sites within the transmembrane (TM) domain of the human sweet taste receptor. We have selected for our studies on the sweetener cyclamate and the antagonist lactisol. We will identify the binding pockets in the sweet taste receptor for sweeteners, and sweet taste inhibitors, that are known to bind in the TM domain, by molecular docking and will test via mutagenesis studies. The model receptor and the docked complexes will serve as initial structures for molecular dynamics simulations in an attempt to understand the underlying mechanism of activation and inhibition of the sweet taste response. The molecular mechanism of agonists and antagonists binding and activation/inhibition of the sweet taste receptor may lead to rational structure based design of novel non-caloric sweeteners, which will aid in the fight against obesity and diabetes. Understanding the taste response mechanisms may also be important for developing new treatment methods for patients with taste malfunctions.