权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Structural Studies on the Cannabinoid Receptor

大麻素受体的结构研究

基本信息

批准号：
7101117
负责人：
Steven Elias Mansoor
金额：
$ 3.03万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-08-01 至 2009-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to understand mechanistically how the neuronal cannabinoid receptor (CB1) becomes activated. Several aspects of this question will be explored. Below is a brief description of my specific aims. (Aim 1) The most widely accepted model for G-protein coupled receptor (GPCR) activation is the two-state model yet recent evidence suggests that this model is too simple to describe GPCR activation. The validity of the two-state model for CB1 activation will be assessed using fluorescence spectroscopy to monitor conformational states of the activated receptor to determine if there is one active state conformation or multiple, distinct conformational states. (Aim 2) Nucleotide binding to docked G-proteins has been shown to affect a GPCR's affinity for its ligands. By exploring whether this is true for the CB1 receptor, I will determine if nucleotide allosteric regulation of ligand binding works through inducing conformational changes in the receptor. (3) The mechanisms by which CB1 is constitutively active will be examined by attempting to make mutations in the receptor that reduce or abolish the constitutive activity. These mutants will then be studied structurally to examine if and how any conformational changes are linked to constitutive activity. Because marijuana is a widely used street drug, and the cannabinoid receptor is a member of the G-protein coupled receptor family (the largest class of drug discovery targets), understanding the mechanism by which the CB1 receptor is modulated is important both clinically and scientifically.

描述（由申请人提供）：拟议研究的长期目标是从机制上了解神经元大麻素受体（CB1）如何被激活。将探讨这一问题的几个方面。下面是我的具体目标的简要说明。 (Aim 1）最广泛接受的G蛋白偶联受体（GPCR）激活模型是双态模型，但最近的证据表明，该模型过于简单，无法描述GPCR激活。将使用荧光光谱法评估CB1激活的双态模型的有效性，以监测激活受体的构象状态，以确定是否存在一种活性状态构象或多种不同的构象状态。 (Aim 2）核苷酸与对接的G蛋白的结合已显示影响GPCR对其配体的亲和力。通过探索这是否是真的CB1受体，我将确定是否核苷酸变构调节配体结合的工程通过诱导受体的构象变化。 (3)CB1组成型活性的机制将通过尝试在受体中产生突变来检测，所述突变降低或消除组成型活性。然后将对这些突变体进行结构研究，以检查是否以及如何将任何构象变化与组成型活性联系起来。由于大麻是一种广泛使用的街头毒品，大麻素受体是G蛋白偶联受体家族（最大的一类药物发现靶点）的成员，因此了解CB1受体的调节机制在临床和科学上都很重要。