G Protein Activation Mechanisms by Hormone Receptors

激素受体的 G 蛋白激活机制

• 批准号: 7212648
• 负责人: Thomas John Baranski
• 金额: $ 26.02万
• 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/7212648
• 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; Personal Satisfaction; 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向细胞发出信号。一般的策略是集中在一个超家族的七个跨膜受体结合激素和介导的信号通过G蛋白。G蛋白偶联受体（GPCR）作为信号转导到细胞中的机制的广泛使用使它们成为药物的频繁靶点;根据一项估计，几乎60%的药物作用于GPCR。这些药物包括常用的处方药，如β受体阻滞剂（心血管）、β受体激动剂（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;近一半的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。尽管它们在生物学和医学上具有重要意义，但受体激活G蛋白的分子机制仍知之甚少。为了解决这些基本问题，该提案采用了多种技术，包括遗传筛选，计算建模和生化分析，以研究人类补体因子5（C5 a）受体，GPCR的视紫红质家族的成员。C5 a受体介导中性粒细胞趋化性，在酵母中表达时功能良好，使得结合激素或偶联G蛋白的受体区域的高通量结构/功能研究成为可能。视紫红质是一种光激活的光感受器，已经通过生物物理分析得到了很好的表征，并且是唯一一种晶体结构可用的GPCR。这两种受体具有相似的结构，使得能够生成C5 a受体的计算模型，并直接测试来自C5 a受体遗传研究的受体活化的特定模型。本提案中概述的研究将深入了解受体如何在细胞中发挥“开/关”开关的作用，从而有助于合理的药物设计，以开发新的治疗药物。