G Protein Activation Mechanisms by Hormone Receptors

激素受体的 G 蛋白激活机制

• 批准号: 7577353
• 负责人: Thomas John Baranski
• 金额: $ 25.99万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7577353
• 关键词: Address; Adrenergic beta-Antagonists; Agonist; Amino Acid Motifs; Antihistamines; Asthma; Binding; Biochemical; Biological; Biological Assay; C5a anaphylatoxin receptor; CXCR4 Receptors; Cardiovascular system; Cells; Chemotaxis; Complement; Computer Simulation; Coupling; Data; Development; Drug Delivery Systems; Drug Design; Family; Family member; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genes; Genetic; Genetic Screening; Goals; Grant; Hormone Receptor; Hormones; Human; Human Genome; Hypersensitivity; Ligands; Light; Mammalian Cell; Mediating; Medical; Modeling; Molecular; Opiates; Orphan; Pain; Pharmaceutical Preparations; Pharmacologic Substance; Photoreceptors; Purinergic P1 Receptors; Receptor Activation; Rhodopsin; Secretin; Signal Transduction; Site-Directed Mutagenesis; Structure; System; Techniques; Testing; Therapeutic Agents; Ulcer; Yeasts; base; calcitonin receptor-like receptor; genetic analysis; human CX3CR1 protein; insight; member; mutant; neutrophil; novel therapeutics; protein activation; receptor; receptor binding; receptor function; yeast genetics

DESCRIPTION (provided by applicant): The long-term objectives of this application are to understand how hormones transduce signals to cells. The general strategy is to focus on a superfamily of seven transmembrane-spanning receptors that bind hormones and mediate signals via G proteins. The widespread use of G protein-coupled receptors (GPCRs) as a mechanism of signal transduction into cells make them frequent targets of pharmaceutical drugs; according to one estimate, almost 60% of all drugs act on GPCRs. These include commonly prescribed agents such as beta-blockers (cardiovascular), beta-agonists (asthma), antihistamines (H1- allergies, H2-ulcers), and opiates (pain). An estimated 3% of human genes encode GPCRs; the ligands remain to be identified for nearly half of the receptors, thus offering many new potential drug targets. Despite their biological and medical importance, the molecular mechanisms by which receptors activate G proteins are poorly understood. To address these fundamental questions, this Proposal employs a variety of techniques including genetic screens, computational modeling, and biochemical analyses to study the human complement factor 5 (C5a) receptor, a member of the rhodopsin family of GPCRs. The C5a receptor mediates neutrophil chemotaxis and functions well when expressed in yeast, making possible high-throughput structure/function studies of regions of the receptor that bind hormones or couple to G proteins. Rhodopsin, a photoreceptor activated by light, has been well characterized by biophysical analyses, and is the only GPCR for which a crystal structure is available. The two receptors share similar structures, enabling computational models of the C5a receptor to be generated and for specific models of receptor activation, derived from genetic studies of the C5a receptor, to be tested directly. The studies outlined in this Proposal will provide insights into how receptors function as "on/off" switches in cells, thus aiding rational drug design for the development of new therapeutic agents.

描述（由申请人提供）：本申请的长期目标是了解激素如何将信号转导至细胞。总体策略是关注由七个跨膜受体组成的超家族，这些受体结合激素并通过 G 蛋白介导信号。 G 蛋白偶联受体 (GPCR) 作为细胞信号转导机制的广泛使用，使其成为药物的常见靶点；据一项估计，几乎 60% 的药物都作用于 GPCR。这些药物包括常用处方药，如 β 受体阻滞剂（心血管）、β 激动剂（哮喘）、抗组胺药（H1 过敏、H2 溃疡）和阿片类药物（疼痛）。据估计，3% 的人类基因编码 GPCR；近一半受体的配体仍有待鉴定，从而提供了许多新的潜在药物靶点。尽管受体激活 G 蛋白的分子机制具有重要的生物学和医学意义，但人们对它们的分子机制知之甚少。为了解决这些基本问题，本提案采用了多种技术，包括遗传筛选、计算模型和生化分析，来研究人类补体因子 5 (C5a) 受体（GPCR 视紫红质家族的成员）。 C5a 受体介导中性粒细胞趋化性，并且在酵母中表达时功能良好，使得对结合激素或与 G 蛋白偶联的受体区域进行高通量结构/功能研究成为可能。视紫质是一种由光激活的光感受器，已通过生物物理分析得到了很好的表征，并且是唯一可获得晶体结构的 GPCR。这两种受体具有相似的结构，可以生成 C5a 受体的计算模型，并可以直接测试源自 C5a 受体遗传研究的受体激活的特定模型。本提案中概述的研究将深入了解受体如何充当细胞中的“开/关”开关，从而有助于合理的药物设计以开发新的治疗药物。