MECHANISM OF AGONISM-ANTAGONISM OF SWEET TASTE RECEPTORS

甜味受体的激动-拮抗机制

• 批准号: 7723183
• 负责人: MENG CUI
• 金额: $ 0.05万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7723183
• 关键词: Agonist; Artificial Sweeteners; Binding; Binding Sites; Bos taurus; Cattle; Computer Retrieval of Information on Scientific Projects Database; Cyclamates; Docking; Family; Funding; G-Protein-Coupled Receptors; Goals; Grant; Human; Institution; Lead; Modeling; Molecular; Mutagenesis; Mutation; Research; Research Personnel; Resources; Rhodopsin; Source; Structure; Testing; Transmembrane Domain; United States National Institutes of Health; base; design; inhibitor/antagonist; molecular dynamics; molecular modeling; novel; receptor; receptor function; response; simulation; sweet taste perception

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of the current proposal is to develop molecular models of possible binding sites for agonists and antagonists within the transmembrane (TM) domain of the human sweet taste receptor, the heterodimer of human T1R2 (hT1R2) and hT1R3, which belongs to the G protein coupled receptor family. Recent crystal structures of bovine rhodopsin provide an opportunity to construct models of GPCRs that have been shown to be reliable predictors of selectivity and of activity in these receptors. We hypothesize that: 1. Agonists and antagonists bind in the same TM pocket; and 2. Through binding, agonists induce specific conformational changes that lead to activation and are blocked by the binding of antagonists. We will identify the binding pockets in the receptor for artificial sweeteners, (e.g., cyclamate) and inhibitors, (e.g., lactisole) by computational molecular docking and test their validity via mutagenesis studies. The experimentally confirmed models will be used to conduct molecular dynamics simulations on occupied and unoccupied receptors to develop an understanding of the molecular basis for activation and inhibition mechanisms of the sweet taste response. The mechanisms inferred from simulations will be tested by mutations designed to produce a constitutively active receptor. These studies should lead to a better understanding of receptor function and will provide the basis for design of novel sweet taste modulators.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 当前提案的目标是开发人类甜味受体跨膜（TM）结构域内激动剂和拮抗剂可能结合位点的分子模型，该受体是人类T1R2（hT1R2）和hT1R3的异二聚体，属于G蛋白偶联受体家族。最近牛视紫红质的晶体结构提供了构建 GPCR 模型的机会，该模型已被证明是这些受体的选择性和活性的可靠预测因子。我们假设： 1. 激动剂和拮抗剂结合在同一个 TM 口袋中； 2. 通过结合，激动剂诱导特异性构象变化，从而导致激活并被拮抗剂的结合所阻断。我们将通过计算分子对接来识别人工甜味剂（例如甜蜜素）和抑制剂（例如乳糖醇）受体中的结合口袋，并通过诱变研究测试其有效性。经实验证实的模型将用于对占用和未占用受体进行分子动力学模拟，以了解甜味反应激活和抑制机制的分子基础。从模拟中推断出的机制将通过旨在产生组成型活性受体的突变进行测试。这些研究应该有助于更好地了解受体功能，并为新型甜味调节剂的设计提供基础。