Structural biology of G protein-coupled receptors

G蛋白偶联受体的结构生物学

• 批准号: 9925243
• 负责人: Vadim Cherezov
• 金额: $ 41.25万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925243
• 关键词: Arrestins; Binding Sites; Biochemical; Biophysics; Cardiovascular Diseases; Cell membrane; Complex; Computers; Data; Development; Diabetes Mellitus; Drug Prescriptions; Drug Targeting; Family; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Human; Human Genome; Immune System Diseases; Laboratories; Ligands; Malignant Neoplasms; Membrane Proteins; Metabolic Diseases; Modeling; Molecular; Molecular Mechanisms of Action; Obesity; Pain; Physiological; Play; Proteins; Research; Resolution; Signal Pathway; Signal Transduction; Specificity; Structure; System; Therapeutic; Translating; addiction; base; design; experimental study; improved; insight; novel; novel therapeutics; programs; receptor; receptor function; receptor-mediated signaling; side effect; structural biology; technology development; three dimensional structure; tool

Abstract G protein-coupled receptors (GPCRs) constitute the largest membrane protein superfamily in the human genome, with over 800 unique sequences. GPCR-mediated signaling pathways play a key role in all physiological systems as well as many pathophysiological conditions, and therefore represent important drug targets. GPCRs have a seven-transmembrane-helix (7TM) topology and contain multiple binding sites for orthosteric ligands and allosteric modulators. Upon recognition of their native ligands receptors transmit signals across the cell membrane to intracellular partner proteins, such as G proteins or β-arrestins. Developing a detailed understanding of functional mechanisms of GPCRs and facilitating design of novel drugs with high selectivity and potency require access to high-resolution three-dimensional structures, determination of which, however, remains a challenging task. We propose here a comprehensive research program which combines technology development with integrated structure-function studies focused on the GPCR superfamily. The proposed research directions are designed to accelerate high-resolution structure determination of membrane proteins, improve our understanding of the GPCR superfamily and answer specific questions on ligand specificity and selectivity, as well as molecular mechanisms of action using several specific receptors as targets. Our approach integrates structural information on new receptors and complexes with data obtained from biophysical, biochemical and functional experiments through computer-based analysis and modeling. The long-term goal of our laboratory is to develop a deeper understanding of the molecular mechanisms of action of GPCRs using the tools of structural biology, and to use the achieved insights to accelerate the design and development of novel and efficacious therapeutics.

抽象的 G蛋白偶联受体（GPCR）构成人类最大的膜蛋白超家族 基因组，具有超过800个独特的序列。 GPCR介导的信号通路在所有人中都起着关键作用 生理系统以及许多病理生理状况，因此代表了重要的药物 目标。 GPCR具有7跨膜螺旋（7TM）拓扑结构，并包含多个结合位点 正常配体和变构调节剂。一旦承认其本地配体接收器传输信号 穿过细胞膜到细胞内伴侣蛋白，例如G蛋白或β-钟RESTIS。开发 详细了解GPCR的功能机制和支持高的新药的设计 选择性和效力需要访问高分辨率的三维结构，确定哪些结构， 但是，仍然是一项挑战任务。我们在这里提出了一个综合研究计划，该计划结合了 通过集成结构功能研究的技术开发集中在GPCR超家族上。这 拟议的研究方向旨在加速膜的高分辨率结构测定 蛋白质，提高我们对GPCR超家族的理解，并回答有关配体特异性的具体问题 和选择性以及使用几个特定接收器作为目标的作用的分子机制。我们的 方法将有关新受体和复合物的结构信息与从生物物理学获得的数据相结合 通过基于计算机的分析和建模进行生化和功能实验。长期目标 我们的实验室是使用使用该GPCR的分子机理的更深入的了解 结构生物学的工具，并利用实现的见解来加速新颖的设计和开发 和有效的疗法。