Mechanism of Agonism-Antagonism of Sweet Taste Receptors

描述（由申请人提供）：当前申请的目标是开发人类甜味受体跨膜（TM）区域内激动剂和拮抗剂结合位点的分子模型。我们选择了甜味剂环己基磺酸和拮抗剂乳酸醇作为研究对象。我们将通过分子对接和诱变研究来确定甜味受体中甜味剂和甜味抑制剂的结合口袋，这些结合口袋已知会结合在TM结构域。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，以试图了解激活和抑制甜味反应的潜在机制。研究激动剂和拮抗剂结合和激活/抑制甜味受体的分子机制，有助于设计基于合理结构的新型无热量甜味剂，从而有助于对抗肥胖和糖尿病。了解味觉反应机制对于开发味觉功能障碍患者的新治疗方法也很重要。

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.