Structure Function of CB1 Cannabinoid Receptor

CB1大麻素受体的结构功能

• 批准号: 10001488
• 负责人: VSEVOLOD KATRITCH
• 金额: $ 71.7万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001488
• 关键词: Address; Affinity; Agonist; Area; Binding Sites; Biological; CNR1 gene; Cannabinoids; Collaborations; Complex; Coupled; Coupling; Crystallization; Development; Drug Addiction; Drug Design; Enzymes; Event; Exhibits; Future; G protein-coupled receptor 50; G-Protein-Coupled Receptors; G-substrate; Generations; Goals; Human; Imidazole; Inflammation; Laboratories; Ligand Binding Domain; Ligands; Lipids; Medical; Metabolic; Molecular; Nociception; Pain management; Pharmaceutical Preparations; Pharmacology; Physiological; Physiological Processes; Play; Positioning Attribute; Preparation; Process; Production; Property; Proteins; Pyrazoles; Research Proposals; Resolution; Role; Signal Transduction; Sleep; Structure; Testing; Therapeutic; Treatment Side Effects; Work; addiction; anandamide; azetidine; base; behavioral study; beta-arrestin; cannabinoid receptor; design; drug candidate; endogenous cannabinoid system; improved; in silico; in vivo; molecular recognition; new technology; novel; novel strategies; programs; prototype; public health relevance; receptor; receptor binding; receptor expression; response; side effect; structural biology; therapeutic development; three dimensional structure; tool

 DESCRIPTION (provided by applicant): Structure-function characterization of a key protein component of the endocannabinoid system, the human cannabinoid receptor 1 (CB1), is the central focus of this research proposal. It aims to develop a fundamental understanding of the structural basis of CB1 function, with the ultimate translational goal of establishing a robust structure-based drug design (SBDD) program based on experimentally determined 3-dimensional structures. The endocannabinoid system is a complex network of lipid ligands, receptors, and metabolic enzymes involved in a wide range of important physiological processes, including nociception, inflammation, sleep, and drug addiction. As with other G protein coupled receptors, CB1 can exhibit preferential signaling events in response to different ligands. This functional selectivity offers the opportunity to discover new medications with improved pharmacological profiles, enhanced therapeutic properties and reduced side effects. The study will provide the structural basis for the design and development of functionally distinct CB1 selective compounds as useful pharmacological tools and/or leads for the future development of therapeutics. Several crystal structures will be solved to better understand molecular recognition, signaling, and to assist in the design of novel compounds that could then serve as prototypes for later generation leads and drug candidates. The study has three specific aims: (1) Design and synthesize covalent ligands representing key classes of cannabinergic ligands that have been shown to have distinct functional profiles, (2) Develop a better understanding of the CB1 orthosteric binding site by solving the 3D structure of several receptor-ligand complexes, and (3) Develop a better understanding of the CB1 active state by solving the structure of the CB1 signaling complex.

 描述（由申请人提供）：内源性大麻素系统的关键蛋白质成分——人大麻素受体 1（CB1）的结构-功能表征是本研究提案的核心焦点，旨在对结构基础有一个基本的了解。 CB1 功能的最终转化目标是基于实验确定的 3 维结构建立强大的基于结构的药物设计 (SBDD) 程序内源性大麻素系统是脂质配体、受体和代谢酶的复杂网络。与其他 G 蛋白偶联受体一样，CB1 参与多种重要的生理过程，包括伤害感受、炎症、睡眠和药物成瘾，这种功能选择性为发现新的配体提供了机会。该研究将为功能独特的药物的设计和开发提供结构基础。 CB1 选择性化合物作为有用的药理学工具和/或未来治疗学开发的先导，将解决几种晶体结构，以更好地理解分子识别、信号传导，并协助设计新化合物，这些化合物可以作为下一代的原型。该研究有三个具体目标：（1）设计和合成代表大麻能配体关键类别的共价配体，这些配体已被证明具有独特的功能特征，（2）更好地了解 CB1 正构结合位点。通过解析几个受体-配体复合物的 3D 结构，以及 (3) 通过解析 CB1 信号复合物的结构更好地理解 CB1 活性状态。